Introduction

Gabriel Richet died on October 10^th 2014. He was ninety-seven years old. His career is intimately linked with the birth of nephrology and its early development. He is considered as a giant in this discipline.

A brilliant dynasty

Borne in 1916 during the First World War, Gabriel Richet represents the fourth generation of an illustrious series of medical doctors, all of them professors at the Faculty of medicine in Paris. His great-grandfather, Alfred Richet, surgeon, took care of the wounded soldiers in 1871 during the siege of Paris by the Prussian army. His grandfather, Charles Richet, was awarded the Nobel Prize in 1913 for the discovery of anaphylaxis. His father, Charles Richet junior, was a specialist in human nutrition and took care, at his return in 1945, of the internees in the concentration camps. On the maternal side, his mother, Marthe Trélat, was one of the first women who became residents in the hospitals of Paris. She was the great-granddaughter of Ulysse Trélat, minister during the Second republic. The aim of Gabriel Richet was to add his first name to those of his ancestors, in which he succeeded beyond all hopes. 

A courageous man during the Second World War and also later

Gabriel Richet was 23 years at the outbreak of the Second World War. He had just become resident in the hospitals of Paris when he was enlisted in the French army and took part to the military campaign in France. He was decorated with the War Cross. After a short captivity in Germany, he was released, came back to Paris and started his activity of resident. All of his family members participated in the struggle against the German occupants. Three of them were deported to concentration camps, his father to Buchenwald, one of his brothers, Olivier, also to Buchenwald, then to Dora and finally to Bergen Belsen, and his cousin, Jacqueline Richet-Souchère to Ravensbrück. At their return, they published a book on their captivity entitled “Les trois bagnes” (The three convict prisons). His mother, Marthe, was jailed at Fresnes, close to Paris. Soon after the liberation of Paris, Gabriel Richet enrolled in the army under the high command of General de Lattre de Tassigny. In the beginning of 1945, fights continued in the South of Alsace where Gabriel Richet served as a doctor in the French commandos. He was wounded in Durrenentzen, a village close to Colmar, received three military citations and was decorated with the award of “Chevalier de la Légion d’Honneur” by General de Gaulle in Karlsruhe in April 1945. After 45 days in a military hospital, he returned to the commandos up to the end of the war and was demobilized in summer 1945. He was attached to Alsace and until his old age he regularly attended the meetings of the veterans of the commandos in Durrenentzen.

The cofounder of nephrology at Necker Hospital

Demobilized from the army, Gabriel Richet joined the department of medicine directed by Louis Pasteur Vallery Radot, a grandson of Louis Pasteur, where he met Jean Hamburger (Figure 1). He was immediately attracted by his personality because at that time, Jean Hamburger was persuaded that the period of a purely clinical medicine was ended and that it was essential to understand the mechanisms of the diseases with new methods based on laboratory and histological investigations such as those in progress in United States. He followed Jean Hamburger in Necker Hospital to establish with him the first French department of nephrology (Figure 2). He worked together with Jean Hamburger during ten years and both are considered to belong to the post-war rebuilders of the French academic medicine. Gabriel Richet after having spent three months in Boston in the department of nephrology directed by John Merrill introduced the treatment of acute renal failure with the artificial kidney and he could with this new method considerably improve the prognosis of this disease associated mainly at this time with post abortum sepsis and crush syndrome. Research studies were carried out and many discoveries were realized, for example the presence of a transient decrease in the number of bone marrow erythroblasts in acute renal failure leading to the hypothesis of a renal hormone controlling red cell production [1]. He also demonstrated that most patients with advanced renal failure died from serious electrolyte changes including hyperkalemia, acidosis and hyponatremia rather than retention of waste products such as urea [2]. Hyponatremia was shown as a consequence of the retention of endogenous water due to lipid oxidation [3]. Introducing the percutaneous kidney biopsy pioneered by Claus Brun in Denmark, Jean Hamburger, Renée Habib and Gabriel Richet contributed to the routine histological diagnosis of glomerular diseases. Together with Paul Michielsen, they performed the first studies of renal histology using electron microscopy. In 1952, Gabriel Richet was involved in the first allogenic renal transplantation from a mother to her son who had lost his unique kidney after a traumatism [4]. The patient was irradiated before the graft in order to attenuate the immunological reject. The kidney graft was not immediately rejected as observed before but, in contrast, kidney function persisted about three weeks opening up exciting new therapeutic perspectives in living related transplantation. In 1955, together with Jean Hamburger and Jean Crosnier, he developed the concept of renal intensive care aimed at correcting disorders of the major fluid electrolyte, acid base and other metabolic functions, thereby markedly improving the prognosis of acute renal failure [5]. The concept was rapidly applied to other medical disciplines leading to the creation of the first departments of intensive care. All these advances were permitted by major technical progresses including rapid determination of plasma concentrations of sodium and potassium with flame photometers, plasma protein separation with electrophoresis, pH meters and new performant optical photometers.

The head of the Tenon school of nephrology

In 1961, Gabriel Richet became head of a department of medicine at Tenon Hospital that he transformed into a department of nephrology over the four following years (Figure 3). To fulfill this objective, he recruited assistants who initially were Claude Amiel, Liliane Morel-Maroger, a brilliant pathologist, and Raymond Ardaillou. He succeeded in obtaining the construction of a new building by the “Assistance Publique-Hôpitaux de Paris” and the University with an intensive care unit, a hemodialysis unit and research laboratories. He could thus develop his team with new members including Jean-Paul Fillastre, Françoise Mignon, Jean-Daniel Sraer, Alain Meyrier, Pierre Verroust, Eric Rondeau and Pierre Ronco (Figure 4). A second wing was built some years later by the “Institut National de la santé et de la recherche médicale (INSERM)” with only research laboratories and Gabriel Richet was appointed as head of an INSERM research unit. Gabriel Richet spent 24 years at Tenon Hospital. It is not possible to describe all the discoveries obtained during this period. Gabriel Richet had his own research program. One of his essential contributions was to demonstrate with Jacqueline Hagège and Manfred Gabe that intercalated cells of the rat collecting duct, also known as dark cells, secreted bicarbonate during metabolic alkalosis and respiratory acidosis and were morphologically different from other cells that secreted H⁺ ions as shown by scanning and transmission electron microscopy. Therefore, he described for the first time the role of specialized cells of the collecting duct in the control of the acid base equilibrium and distinguished the A and B types of intercalated cells showing that they were different functional forms of the same kind of cells [6]. He also studied with monoclonal antibodies made in the laboratory Tamm Horsfall protein in plasma and urine of patients with renal diseases [7]. He participated in many clinical studies with his collaborators. Thereby, his goal to create in Tenon hospital a department of national and international excellence for renal diseases was largely reached. Moreover, he succeeded in stimulating research in other disciplines and the hospital which was at his arrival an establishment uniquely devoted to clinical activities became a center of investigations and research. He frequently proposed to his collaborators unsolved questions as new topics of research. Like in the parable of the sower, many grains of wheat died, but some of them sprang up and allowed new discoveries to be done. In fact, he let a great freedom to his associates in the choice of their own research project, followed the progress of their research with much interest and was very happy when they reached international recognition.

An international and national recognition

Gabriel Richet is one of the early giants of French and international nephrology. He was a founding member of the international Society of Nephrology (ISN). Among his many roles in the leadership of ISN, he was co-General Secretary of the ISN’s first Congress in Geneva and Evian in 1960 chaired by Jean Hamburger, and ISN President from 1981-84. He received many awards including Honoris Causa Degrees; among those awards, the most prestigious probably was the Jean Hamburger Prize of the ISN in 1993. His fame could be measured by the large number of fellows and visiting faculties from countries all over the world, who trained or did research in this multilingual and multicultural Tenon community, a virtual nephrological tower of Babel. Gabriel Richet provided a unique atmosphere of intellectual curiosity and creativity by providing support and guidance to each of them, while at the same time leaving the freedom to all to develop their own projects. Thanks to his generosity and his warm personality all who worked with him would consider him as a “father” figure, a position that he accepted and filled with a lot of humor and joviality. Thus doctors from around the globe will remember him with warmest personal feelings, and each could contribute an anecdote testifying to his humanity, tolerance and personal support. It is not possible to cite all of them, but only those with whom permanent links were established such as Detlef Schlondorf, Morris Schambelan and Gary Striker (USA), Stanislas Czekalski, and Hanna Debiec (Poland), Emilio Podjarny (Israel), Kiyoshi Kurokawa (Japan), Diego Lopez Novalez (Spain), Vicky Cattell (UK), Judith Withworth (Australia), Vadislav Stefanovic and Milos Budislavjevic (Yugoslavia), Lise Giroux (Canada), Pierre Cosyns (Belgium), Hedi BenMaiz (Tunisia), Tullio Bertani (Italy). Gabriel Richet was particularly attached to the relations with China. His department welcomed many students including Nan Chen who is now head of the department of nephrology at Rui Jin Hospital in Shanghai and John Cijiang He who is professor of nephrology at the Mount Sinai Hospital (New York). Gabriel Richet was appointed Grand Officer of the French Legion of Honour by the French government in 2012 (Figure 5).

The legacy

When Gabriel Richet retired in 1985, he left as a legacy, two departments of nephrology, one for the patients with chronic renal failure and those treated with hemodialysis, the other for transplanted patients and patients with acute renal failure, a department of clinical investigation in ambulatory patients and a research unit depending of INSERM. All of them were directed by his former collaborators. Moreover, several others became heads of departments of nephrology in different cities of France including Rouen, Limoges and Evry. He started annual meetings where they all met for discussing difficult patient records including the histological data.

The retired nephrologist and historian of medicine

After his retirement on September 1^st 1985, Gabriel Richet was an active member of the National academy of medicine. He was interested by improving the conditions and methods of teaching in the medical faculties and cosigned several reports on this question for the government. He also devoted much of his time in historical studies, mainly on the history of nephrology and on the work of his grand-father Charles Richet. He published articles on the discovery of anaphylaxis [8], the report written by Georges Cuvier on the situation of public health in France at the time of the 1^st Empire [9], the nephrolithiasis at the turn of the 18^th and 19^th centuries [10], the work of Pierre Rayer who was a precursor in the studies of renal diseases [11] and Bonaparte’s expedition in Egypt [12]. A particular mention has to be done on his studies with Italian colleagues interested in the history of medicine. Together with Carmela Bisaccia and Natale G de Santo, he studied the renal stones of Montaigne [13], the medicine in the “Encyclopédie of Diderot et d’Alembert” [14], the build-up of clinical science [15], Desault and the birth of nephrology [16], the contributions of Bertin [17] and Ferrein [18] to renal histology. This enumeration shows that Gabriel Richet continued to work many years after his retirement. He also received at home his ancient collaborators and discussed with them the results of their recent studies.

The man

What was the real personality of Charles Richet? He describes himself in his last lecture at Tenon Hospital in October 1985 as a distressed intellectual (“un angoissé intellectuel”) who from the beginning of his medical career refused to be satisfied with a purely descriptive medicine, but was distressed by the thirst for knowledge, which directly accounts for two others of his qualities: his eagerness to work and his open mind to understand others. When he recruited a future resident, the two qualities to which he was the most sensitive were imagination and the taste for working. He searched in the others his own characteristics. Like Alceste, the main character in the”Misanthrope” by Molière, Gabriel Richet could have said “Je veux que l’on soit homme, et qu’en toute rencontre, le fond de notre coeur dans nos discours se montre” which could be translated into “I want to see a man in any one of us, and at every encounter, words show the depth of our heart”. Gabriel Richet was essentially a generous man who showed a real interest for the life of his pupils and assistants. He was proud of their successes and sad of their failures. He will remain for the medical community an example of cleverness, humanism and nobility of character.

Background

Hugh de Wardener, Figure 1, previously Professor of Medicine at Charing Cross Hospital Medical School, London, died on the 29^th September 2013, just ten days before his 98^th birthday I knew him for over 50 years as a student, junior doctor, consultant colleague and friend. He had a very varied life in relation to his background and his personal and professional life.

Hugh was born in Paris in 1915 whilst World War 1 was raging. War was to play a significant role in his future. His father was Baron Edouard de Wardener, a Frenchman with Austrian and American links. His mother was American – a doctor’s daughter – with French links. The marriage ended when he was 1 year old. Thereafter he travelled with his mother, mainly in Europe. He attended schools in various places: Lausanne, Rome, Florence, Albuquerque and, in the UK, in Sussex and then Malvern College. He spoke no English until age 8.

He was born Edouard Hermes Hippolyte! His mother, perhaps not surprisingly, got rid of the middle names. As a schoolboy Hugh was very keen on the “Bulldog Drummond” books, the hero of those stories being Hugh Drummond. Hugh decided to change his names to Hugh Edward when he was naturalised British in 1938.

He first studied with engineering in mind but, knowing that his mathematics was poor, he went into Medicine and studied at St Thomas’s Hospital Medical School, qualifying in 1939. His first post was as House Physician at Scunthorpe Memorial Hospital in Lincolnshire. Soon after starting his consultant was killed in a road accident and Hugh was left in charge of adult medical and paediatric patients for the remainder of the post.

Prisoner-of-War

de Wardener enlisted in the British Army and thence into the Royal Army Medical Corps (RAMC). He was posted to Singapore but the island soon fell to the Japanese army so that in February 1942 he became a prisoner-of-war (POW). After a year at a hospital in Singapore, dealing mainly with dysentery cases, he was moved to work on the Burma-Siam (now Thailand) railway, later made famous by the film “Bridge on the River Kwai”. At various camps he dealt mostly with infections: dysentery, cholera, diphtheria and malaria; the sufferers had superimposed severe malnutrition. With a pathologist, who, amazingly, was allowed to carry out autopsies, he discovered that quite a lot of patients had developed Wernicke’s encephalopathy. The changes in the brains of prisoners who died were typical of this condition. There was clearly no association with alcohol in these POWs, as was the accepted aetiology. de Wardener found that the Wernicke’s in his patients was due to vitamin B1 deficiency. Treatment with “Marmite”-a beef extract-and, when available, parenteral vitamin B1, resulted in huge improvements in the patients’ condition.

de Wardener kept detailed records of his cases and hid them in a large tin which was sealed and buried in the grave of a prisoner. Bearings of the grave were taken using trees as markers. When the war ended he was able to retrieve the tin, notes intact, and bring the records back to England.

Hugh’s clinical care of fellow POW’s was highly regarded. One prisoner who survived illness and captivity wrote a book after the war which he dedicated to de Wardener amongst others. He described him as “one of the most respected figures in Thailand” and wrote “His soft, level voice sounded as sympathetic as it did effective, and after half a minute I felt as if a great weight had been lifted off my chest…my neighbour whispered ‘there’s no need to worry any longer these days, Ginger’s got it properly under control. No one has died for several days.’ [1] Ginger was Hugh’s nickname on account of his hair colour.

Hugh’s personal views about his medical role were different: “I was lucky to be a POW and a doctor. We were lucky to do our job and not to have to do any of the horrible work, the hard labour. I had wonderful experiences seeing things I could write up”. And “As a doctor you can’t often say that you really save lives; you are about when they recover… you do the right thing… and they recover. Just occasionally, perhaps two or three times in your life, you actually make a difference” (personal communications).

Hugh “made a difference” to many people’s lives while in captivity. He undoubtedly saved many lives but rarely talked of it and never in those terms.

But in captivity he also showed a talent of a different kind-acting. On Christmas night 1943 he starred in a show entitled “Babes in Thailand”. It was written of him “An RAMC officer, Captain Hugh ‘Ginger’ de Wardener, was in the cast… His performance as the ‘Fairy Queen’ on that first night is the stuff of legend… He and others went on to produce many more shows and revues which helped keep morale and spirits high… For a brief moment in the middle of our dark jungle they brought us a shaft of light, a breath of freedom” [2] [3].

de Wardener’s war-time medical work revealed his determination to use his experiences for the greater good. He returned to England in 1945 and, using the previously buried records, wrote two papers, published in the Lancet in 1946 and 1947. One was on cholera [4] and the other on Wernicke’s encephalopathy or Cerebral Beriberi as it was entitled [5]. His work as a POW was recognised by the award of a Military MBE (Member of the Order of the British Empire).

St Thomas’s, Charing Cross, and after

After a period of illness-TB contracted in captivity- de Wardener returned to St Thomas’s and was soon researching and publishing. The basis for his long and glittering career in Nephrology was his interest in and understanding of renal physiology. His interest in renal sodium transport started at St Thomas’s and continued at Charing Cross where he had been appointed first Professor of Medicine (University of London) in 1960. His pursuit of a “third factor” affecting renal sodium transport – the Natriuretic Hormone (NH) – occupied much of his time and paper-writing. His first such paper was entitled “Renal function during emotional diuresis” [6]. I do not know what the emotion entailed, but the paper showed that the lady had a massive natriuresis when catheterised. The authors hypothesised that this was due to a factor other than changes in GFR or aldosterone, i.e. the “Third Factor”. Subsequently he confirmed, in man and animals, that blood volume expansion caused natriuresis without changes in GFR or aldosterone.

de Wardener’s hypothesis was initially ridiculed by some. He described how comments were made to him en passant at meetings such as “Where’s the white powder, Hugh?” Initially the hormone was thought to be a protein, then a peptide. Other experiments suggested the hormone was released from brain tissue and later that it was a Na-K-ATPase inhibitor. Ultimately de Wardener was unable to identify the nature of NH but, as is now well known, the work of others has confirmed that not only does a” third factor” exist but that renal sodium transport is multifactorial in its control.

Hugh had many other research interests. These included renal infection, renal histology, maintenance haemodialysis (his phrase), renal and metabolic bone disease, and calcium, vitamin D, aluminium and magnesium metabolism. He retired from clinical work in 1981 but persisted with his interest in sodium, publishing many papers with Professor Graham MacGregor on the relationship between sodium and the aetiology of essential hypertension.

He published papers every year from 1946-1997- a half century of work-and continued to publish until 2012 at the age of 96.

He achieved much else. In 1958 he wrote the first textbook dedicated to renal function and diseases, typically and simply titled “The Kidney”. He single-authored five editions of this book, the last being in 1985. Whilst at Charing Cross, with others, he developed a computer programme for the recording and tracking of clinical, haematological and biochemical data from dialysis patients. This system still forms the basis of many such programmes in use today in renal and other specialities.

Hugh never relinquished his clinical work. He remained an “on-take” general physician as well as an active clinical nephrologist until he retired from clinical work in 1981. He always turned up for his ward rounds and clinics. His patients loved and respected him. He was a personable and charismatic man. Lady patients often had their hair done prior to his rounds! He always recognised the personal needs of patients and in 1972 was responsible, with others, for establishing an independent holiday dialysis facility on the south coast of England. The centre provided accommodation for three or four families and there was a resident nurse who took over dialysis treatment from the patients and/or carers. The centre is still in use today.

Awards and Recognition

de Wardener’s contributions to medicine, and nephrology in particular, have been recognised in many ways and in many countries. He was actively involved in the early days of the International Society of Nephrology (ISN) and helped in the planning of “Nephron” and “Kidney International”. He worked with Professor Richet in this task and they published their proposals and agreements. He was ISN president 1969-1972 and president of the UK Renal Association 1975-1978. He was elected to various medical societies in Great Britain, Europe and the United States. He was the recipient of many awards including the Hamburger Award in 1993 (jointly with Professor Richet), the Homer Smith Award 1972 and the Franz Volhard Award 1996. He was made CBE (Commander of the Order of the British Empire) in 1981.

In Hugh’s obituary in Kidney International Bob Schrier-who had worked at Charing Cross with de Wardener in 1967-1968- wrote: “He was always a role model for me as a charismatic teacher, innovative researcher and caring physician. He was always inquisitive, asking why and how. His dedication to his patients’ welfare was exemplary. He lived a remarkable and full life. He will be direly missed” [7].

Hugh died on de Wardener Ward at Hammersmith Hospital on 29^th September 2013. Perhaps not surprisingly he left his body for medical research. He was a great man and a great scientist and certainly part of the History of Nephrology. To me he was a doctor who truly practised the art and science of Medicine.

Introduction

Diseases were, and still are the major cause of human loses during the wars throughout the ages, from ancient till current times. Not that long ago, during the Civil War in America up to 63% of military service man on Union and Confederate side died due to diseases.

Statistics for the World War I shows, that out of 17.5 millions military service people who died on both side, approximately 10 millions death were still caused by diseases. Half of the American Expeditionary Forces deaths (56,991 out of 116,516) during that World War I were related to diseases, with pneumonia accounted for 83.6%, meningitis 4.1% tuberculosis 2.3%, empyema 1.1%, septicemia 0.6%, and Bright’s disease 0.5%.

Special worry for the military leaders is always caused by appearance during the war a new or looking like new disease with unknown consequences to the readiness of the military forces.

A nameless correspondent in Northern France for the British Medical Journal in 1915[1] described as a “new disease”, nephritis with general dropsy, among British soldiers returning from trenches. Subsequently, the word “new” was removed from the description of the nephritis following a short letter to the editor of BMJ [2]. But the epidemiology and clinical course of this nephritis was so greatly different from the one observed in the civilian population that the distinct name of “trench nephritis” was given for this illness. Other trench derived disorders recognized at the time of World War I were “trench fever” (five day fever) caused by bacterium Bartonella quintana and “trench foot”, medical condition caused by prolonged exposure of the feet to damp, unsanitary and cold condition common in trenches.

Trench War (1914-1918)

During the Great War the western front was in stalemate from September 1914 till spring 1918. Trenches, 475 miles long, crossed the France from the Swiss border in the south to the North Sea coast of Belgium. Despite thousands of attempts by the Entente and German troops to cross the lines of trenches they barely moved more than 5 miles in each direction. Trenches were from 6-9 to 25 feet deep, composed of three lines of 150-200 feet apart. The first line was for sentry group, next for the main garrison and the third one for support troops. The “no man land” between the enemies was as narrow as 10 yards, but on average 100-400 yards. Routine trench cycle for the soldiers included 70 days in front line, 30 days in nearby support trenches, and 70 to 120 days staying in the reserve.

Trenches accumulated muddy water during heavy rainfall and required water to be pump out. Rats (brown and black variety), which in millions infested trenches, were more than a nuisance and lice were another never-ending problem.

A letter from the trenches written by the soldier in 1916 describes the life in trenches: I joined the army for adventure and the chance to see new places but… I am living in mud hole, freezing… fear of death. Every day I have spent in these trenches, we have had shells fired on us. The mud brings trench foot with it… your feet swell up sometimes double their original size… Men will often have the foot amputated rather than endure the terrific pain. Trench foot isn’t the only illness that is rife amongst soldiers… Nephritis (kidney inflammation)… are very common …every single man in this trenches has lice… Masses of bodies are piled up… Rats feed upon the corpses” [3].

William Osler as a Nephrologist

There is no doubt that William Osler (Figura 1) was the most recognized and reverent physician of his time. He left more than 1600 items encompassing medical, philosophical, educational, and historical papers. Despite the fact that many potential readers of this paper are very likely familiar with his biography, and his major achievements, I will briefly reflect upon his life and his contributions to nephrology.

He was born in rural Canada in 1948 (Table 1). Fascinated by the potential of the microscope in the enhancement of science and directed by his teachers he decided to study medicine at McGill University. After finishing a trip to the major European medical centers, a frequent practice at that time for American young physicians, Osler was appointed as a pathologist to Montreal Hospital and as a professor of the Institute of Medicine to teach medical students in the area of pathologic histology. Osler followed Virchow’s approach to clinical medicine and used pathology/autopsy findings for an explanation of clinical signs and symptoms. He did over 1000 autopsies at McGill (1874-1884). His introductory remarks to the course of microscopic studies included the statement “in no class of diseases is it of greater service than in the various renal disorder. Here we may not only date the commencement of the affection, and follow it in its progress, but also, very often obtain tolerably certain evidence of the nature of the changes going on in the kidney (1876)”. In 1883 he described urinary findings in two cases of “puerperal convulsion or eclampsia gravidorum” and discussed the “peculiarities on the nephritis of pregnancy” such as “rarely any fever, no pain in loins”, “the amount of albumen is very large. At least 25% of these patients may have convulsion [4]“. Other papers, in the field of nephrology published by Osler, include topics such as kidney tumors, polycystic kidney, renal cirrhosis, uremic syndrome and collagen vascular disorders. In 1890 Osler published two cases of acute nephritis in typhoid fever [5]. Finally the modern textbook which William Osler published The Principles and Practice of Medicine in 1892 deserves special remembrance. He considered chronic Bright disease to be distinct from acute form; subdivided chronic form into various categories and delineated causative factors for some kidney diseases related to gout, lead, atherosclerosis and ageing.

During his professional life Osler occupied the most prestigious positions American medicine. He was a professor of clinical medicine at University of Pennsylvania (1885-1889), professor of medicine at John Hopkins (1889-1905) and Regius Professor of Medicine at Oxford in 1905.

Osler Engagement in the War Effort

Osler learn about the eruption of World War I while he was at the sea heading for Canada together with his wife and son. They returned to England on August 22, 1914. Osler strongly supported the British and Canadian war effort. He visited military camps and hospitals, giving lectures and encouraging vaccinations for the military personnel. He was Physician-in-Chief at the Queen’s Canadian Military Hospital at Shorncliffe, a consultant to the American woman’s auxiliary hospital at Paignton, and served as head physician in Canadian Red Cross hospital [6]. His son initially joined medical unit in 1915 but later asked to be transferred to artillery and was killed by the shrapnel in Belgium on August 24,1917. Osler was devastated by this news delivered to him by his friend and colleague Harvey Cushing.

Trench Nephritis at the Royal Society of Medicine Meeting, year 1916

Osler was invited for meeting held at the Royal Society of Medicine in February 1916 in London and was one of four speakers at that conference [7]. Dr. W L Brown was the major presenter. He was a leader of the team established by Medical Research Committee to investigate cases of “trench nephritis” in the wards under his care at St. Bartholomew’s Hospital in London. He started with statement that during American Civil War in the Central Region the incidence of nephritis was quite prevalent of 0.15% (total of 14.187 cases). There were 1062 cases of trench nephritis observed in the British Expeditionary Forces up to June 1916. WL Brown’s personal experience came from a detailed analysis of 58 cases followed at his ward. He considered a different etiology of the diseases including toxic agents, microbial infections and exposure not committing himself to either one. Throat streptococcal infection was strongly consider as a cause knowing association of nephritis and tonsillitis, but he found low level of streptococcal antibodies in his cohort making this option less likely.

The clinical presentation of trench nephritis was not rigorously studied. Some soldiers presented with headache, vomiting, sore throat, marked shortness of breath. Irregular temperature was common occasionally up to 103^o F, 24-48 hours ahead of proteinuria.

Edema localized to face and legs was reported at presentation in 53 out of 58 cases. It lasted 4-5 days, sometimes longer. Frequent presentation was dyspnea (pulmonary renal syndrome?). Bronchitis was prevalent, heart was normal on physical examination, but occasional ascites was noted. Volume of urine was variable; often markedly increased; the oliguria was unusual (as opposed to ordinary acute nephritis). Proteinuria mostly was non-nephrotic, non-selective and with frequent macroscopic hematuria (54 out of 58 cases). Renal pathology in few fatal cases show evidence of subacute diffuse nephritis with inflammation and extensive damage to convoluted tubules. By Dr. Brown assessment, the prognosis for recovery seemed to be good. Only one patient out of 58 died, but he worried about possibilities of relapse. As a treatment he suggested to adopt diet poor in nitrogen for a short period of time, but he was against prolonged nitrogen starvation.

He noticed the publication of the bigger study by John R Bradford [8] published in January 1916, which basically confirmed his observations. It was an analysis of 571 out of 1455 cases of trench nephritis treated in base hospitals in England since April 1915 till 1916.

William Osler was the second speaker. He summarized the clinical presentation of trench nephritis based on his personal experience. He found the sudden appearance of swelling with rare cases of anasarca quite typical. Fever was not a common early presentation in his experience. He found rapid improvement in most of the cases during hospitalization but questioned the overall good prognosis for the trench nephritis forwarded by WL Brown.

“Restoration of good health, with the persistence of a large amount of albumin, of blood, and of cast, with increasing high blood pressure, is an unusual combination in the nephritis of civil life, yet that has been common enough in these cases”. Specifically “Cases which are lasting from twelve to fourteen weeks, the chances are that it will become subacute or chronic…” “I fear that a considerable proportion of the cases we have at present under observation will pass on to the chronic stage”.

The cautionary approach to long term prognosis [9]expressed by Osler did find confirmation in the study arranged by the Ministry of Pension in UK. The observations of 5210 cases between 1920 and 1926 show that complete recovery from trench nephritis occurred in 36% of cases, while 19% had albuminuria, 11% profuse albuminuria, 15% chronic nephritis with hypertension, 12% classic glomerular nephritis and 5.5% hypertension only. Once again the genuine mind and experience of Osler prevail.

Introduction

Many basic scientists have paved the way leading to our present understanding of electrolyte and acid-base balance, and in finding a rationale for normalizing its disequilibrium. Among them Jacques Loeb (1859-1924) had a preeminent role.

Jacques Loeb (Figure 1), from Maiden in Prussia, was born to a family of Jewish immigrants from Portugal at the time of the Inquisition. He attended the Askanische Gymnasium in Berlin, and studied medicine in Strasbourg where in 1884 he got his MD.

Subsequently he worked with Nathan Zunz (a precursor physiologist of altitude and aviation) in Berlin, and with Adolf Fick (Figure 2) in Würzburg. There he also learned a lot on plant physiology from the charismatic botanist Julius von Sachs (Figure 3). Finally he was ready to take over the assistant position made available by Friedrich Goltz in Strasbourg.

In the years 1889-1891, Loeb worked at the Marine Zoological Station in Naples. At the age of 32 years, he moved to the United States where he later became professor and chief at the Universities of Chicago, California at Berkeley, and the Rockfeller Institute in New York. There he founded and co-directed till death, the Journal of General Physiology.

When he moved to his final position in New York, he had clear in mind the concept of translational biology. In fact he had written to Simon Flexner, the first director of the Institute, “in my opinion experimental biology – the experimental biology of the cell – will have to form the basis not only of physiology but also of General Pathology and Therapeutics”.

One can read this from a letter published in the landmark biography of Loeb by H.J.V.Osterhout[1].

Loeb aimed to apply physico-chemistry methods to the understanding of biological processes and explored the physiological effects of ions. In fact The Journal of General Physiology was created for papers “devoted to the investigation of life transport processes from a physico-chemical view-point. […] The Editors invite contributions relating to the physic-chemical explanation of life phenomenon, no matter in what field of science they originate.” [2] (full text).

It should be noticed that he did personally the major part of the experiments that appeared in literature. In the bibliography compiled by Nina Kobelt [3] it emerges that he published a total of 404 papers. For 363 of them he was the only author. In 40 papers there was 1 collaborator (for the majority of them Hardnolph Wasteneys). Only in one paper his name is associated with two coauthors.

The importance of Loeb’s early studies in Naples for subsequent achievements in life

Loeb went to the Zoological Station of Naples (Figure 4) on October 10, 1889 and left it on April 24, 1811. A working table was granted by the University of Strasbourg. Loeb arrived in Naples to work in a young prestigious institution that was newly established by Anton Dohrn on the sea shore of Naples.

The institution under the prestigious director (Figure 5), a fervent Darwinist, attracted scientists all over the world, because of its system based on Working Tables. This system was financed by governments, universities, scientific institutions from all over the world.

There the investigators were granted working facilities, living biological material from the Mediterranean sea and an enthusiastic environment for research that was nurtured personally by Anton Dohrn.

“The winter of 1889-90 he spent in Naples carrying on experiments on heteromorphosis and the deep migration of animals (in the latter in collaboration with Groom [4] and it was there that he became interested in America through his contact with Henry B Ward and W. W. Norman” [1].

We can say that Osterhout [1] failed to illustrate the fact that, at the Zoological Station of Naples, the physiologist, using the methods of a marine biologist, was turned into a biophysicist.

Naples was the place where Loeb’s interest in marine biology was nurtured. So the studies at station Dorhn are the roots for research which granted him, later in life, an international reputation (he was even on the list of potential recipients of the Noble Price, however he was not awarded it). Indeed the atmosphere at the newly founded zoological Station of Naples was stimulating. There was time for exchange between scientists and great visitors which made the place unique. Anton Dohrn (Figure 5) was there to help nurture the creativity of those young international scientists. However, there were also renowned university professors.

During the stay of Jacques Loeb at the Zoological Station in Naples a total of 119 working tables were occupied, 2 by students, 93 by young investigators from all over the world, and 24 from full university professors. Among them were Felix Hoppe Seyler (1825-1895), the founder of biochemistry, and Wilhelm His Sr (1831-1904), the Swiss anatomist professor in Lipsia. So in the years 1889-1891 at the Station the ratio between young investigators and academicians with a track curriculum was around 4 to 1. It should be noticed that there were only 3 Italian professors, one of them being from Naples (Table 1).

Aims

The goal of this study is to illustrate the contributions of Jacques Loeb to the understanding ion movements in the living organisms.

Results

Defining a general law of mineral equilibrium for preservation of life

In a study of 1906, Loeb studied the stimulating and the inhibitory effects of magnesium and calcium upon the rhythmical contractions of a jellyfish (Polyorchis). He used as a model either the animals living in the Bay of San Francisco, or the isolated centre of this medusa that was deprived of its margin containing the sense organisms and the central nervous system [5] [6].

He showed that

1. “The spontaneous normal swimming motions of Polyorchis occurs only in presence of magnesium and that, their occurrence in sea water is due to the presence of magnesium in rather high concentration. […] The effect of magnesium can be inhibited by the addition of an equivalent amount of calcium or of potassium”
2. “A pure solution of calcium chloride will cause the isolated centre to beat rhythmically, whereas it does not beat in normal sea-water. […] The calcium acts in the same way when added to a sodium chloride solution” […]. It requires much less barium chloride than calcium chloride to call forth immediately rhythmical contractions of the isolated centre in a sugar solution. […] Strontium chloride also calls forth the rhythmical contractions of the centre when added to sea-water, sodium chloride solutions, sugar solution and distilled water. […] It was practically impossible to produce rhythmical contractions by magnesium chloride”
3. “The decalcifying salts cause rhythmical contracts”
4. “Acids cause the isolated centre of Polyorchis to beat, while alkalies have the opposite effect”. […] Acid has the same stimulating effect when added to sea-water, only much more acid must be used than in sodium chloride, because of the presence of bicarbonates and magnesium chloride”
5. “Sea-water is considerably less injurious than the addition of an equivalent amount of calcium”

The role of salt for preservation of life

Loeb did seminal experiments on this topic and some intriguing results were published in Science in 1911 [4] and in the Journal Biological Chemistry in 1914 [7].

In Science he started pointing out that

1. “Less is known of the role of salts than on the role of the three main food-stuffs, namely carbohydrates, fats and proteins. As far as the latter are concerned, we know at least that through oxidation they are capable of furnishing heat and other forms of energy. The neutral salts, however, are not oxydizable. Yet it seems to be a fact that no animal can live on an ash-free diet for any length of time, although no one can say why this should be so”.
2. “The cells of our body live longest in a liquid which contains 3 salts, NaCl, KCl and CaCl₂ in a definite proportion, namely 100 molecule of NaCl, 2.2 molecules KCl and 1.5 molecules of CaCl₂. […] NaCl, KCl and CaCl₂ exist in our blood in the same relative proportions as in the ocean. […] KCl and CaCl₂ are only necessary to prevent the harmful effects that NaCl produces if it is alone in solution and if the concentration is > 1/8 M. […] NaCl and KCl alone cause abnormal contractions of the heart which are rendered normal by the addition of CaCl_2. […] A mixture of NaCl + CaCl₂ also causes abnormal contraction of the heart, but they are rendered normal by the addition of KCl”.
3. “We are dealing, in other words, with a case of antagonistic salt action; an antagonism between NaCl in one hand and KCl and NaCl on the other. The discovery of the antagonistic salt action was made by Ringer who found that there is a certain antagonism between K and Ca in the action of the heart. Biedermann had found that alkaline solutions cause twitchings in the muscle and Ringer found that the addition of Ca inhibited these twitchings” […]. “If we put the eggs of Fundulus immediately after fertilization into a pure sodium chloride solution which is isotonic with sea-water, they usually die without forming an embryo. If however only a trace of a calcium salt or of any other salt with a bivalent metal is added to the M/2 NaCl solution, the toxicity of the solution is diminished or even abolished. […] Not only the bivalent metals are able to render the sodium chloride solution harmless, but the reverse is also the case, namely that NaCl is required to render the solution of many of the bivalent metals, harmless. […] The antagonistic action of salts consists in a modification of the egg membrane by a combined action of two salts, whereby the membrane becomes less impermeable for both salts”.

With pride he added that:

“In a series of papers beginning in 1900 [8] – Figure 6 – I have shown that:

• (a) It is necessary for the normal functions of living organs and organism that the ration of the concentration of antagonistic ions (Na+K/Mg+Ca) of the surrounding solution be kept within certain limits. If the value of the quotient becomes either too high or too low, life phenomena become abnormal and finally impossible [9]”.
• (b) The salts to be considered as antagonist in this sense are in the first place those of univalent and bivalent metals and that therefore the most important critical quotient will generally be C_Na+K/C_Mg+Ca
• (c) There is also an antagonism between the salts of bivalent ions such as Sr and Mg and Ca. This was the genesis of Loeb’s General Law of Mineral Equilibrium [9] (Figure 7).

“Life phenomena as a rule take place in a medium whose composition and concentration undergoes little or no variation, such as sea water or blood serum and the majority of the organisms cannot stand any wide variation from this fixed standard C_Na+K can be considered only the lower and upper limit for C_Mg+Ca can be determined for this value”_. He then tried to assess the possible lower and upper limit of C_Mg+Ca change when C_Na+K varies, and showed that it occurs in accordance with Weber’s law [10].

The physiologically balanced salt solutions

He demonstrate since 1900 that water of the sea as well as blood are physiologically balanced by a mixture of “96 cc. 5/8 N NaCl + 2 cc. 10/8 N CaCl₂ + 2 cc. 5/8 N KCl”. Years later he defended his primacy in a letter to Journal Biological Chemistry [11].

The effect of acids

Loeb had a great continuous interest on the effects of acids [12] [13] [14] [15]. In 1911 [6], Loeb in Science reported about the first time upon experiments he had made with Mr. Wasteneys on the toxic action of acids upon Fundulus and showed that “the toxic action of acids can be annihilated by salts”. They showed that “not only butyric acid, could be rendered harmless by neutral salts, e.g., HCl by NaCl”, They also showed that CaCl₂ was “8 to 11 times as great and powerful as the action of NaCl”.

It is of interest to stress that at that time Loeb had developed the idea that “each cell may be considered a chemical factory. Its work depends on the diffusion of substances into the cell is restricted if its composition is not made of fats”. “The antagonism between acids and salts suggests the idea that the surface film of cells consists exclusively or essentially of certain proteins”.

Loeb published data on the addition of acid to 4 days old eggs of Fundulusin distilled water and to eggs in salt solution. He added acetic acid (M/500) in order to measure the time to heart standstill of the embryo in the egg [16].

“It was found that the time in which the hearts stopped beating was much shorter when acid was added to distilled water than when it was added to salt solutions” […]. “We will show that the protective action of salts is a distinct function of the nature and valency of the anion”. In fact “the organic anions and the bivalent one being much more efficient than inorganic univalent anions Cl, Br, I and NO₃. The antagonistic action of salts with bivalent cations is very much greater than that of the univalent cations, CaCl₂, and to some extent MgCl₂ are much stronger antagonists to acid than were the chlorides of monovalent metals”.

“The presence of acids also retards the diffusion of calcium into the egg”. “To kill the embryo the acid must diffuse through the membrane of the egg and the question arises whether the salt in the outside solution inhibits or retards this diffusion or whether it diffuses with the acid into the egg and prevents the injurious action of the acid upon the embryo inside the membrane”.

Loeb concluded

1.  It is shown that salts inhibit the toxic action of acids upon the embryo of Fundulus.
2. This inhibitory action of salts is a function of the anion as well as the cation. Rhodanates, acetates, sulphates and tartrates inhibit very strongly, chlorides, bromides and nitrates much less, and iodides least of all. The bivalent cations Ca and Sr and to a smaller degree Mg also inhibit more strongly that the univalent cations.
3. The antagonistic action of the anions retarded the rate of diffusion of the acid through the membrane [16].

A general salt effect can be demonstrated also for the diffusion of acid through the membrane of Fundulus egg. The concentration of neutral salt required for the salt effect is considerably smaller in the case of diffusion of an acid than in the case of diffusion of potassium salt. Very weak acid solutions can supply the general salt effect. When the concentration of neutral salt added to the acid is a little higher, the diffusion of acid is retarded or inhibited (antagonistic salt action).

From Osterhout [1] we learn that “Loeb found that to a certain extent the behavior of potassium in entering the cells paralleled that of the acid. He observed that weak acids and bases appear to penetrate much more rapidly than strong ones, indicating that the protoplasm is not readily permeable to ions […]. Later studies demonstrated that “The importance of hydrogen ions lies in the fact that in alkaline solutions the protein acts like an anion but in sufficient acid solutions it behaves like a cation. At the isoelectric point the two actions are approximately equal” [17].

This caused the inclusions of hydrogen ion in equation 1 which became the final equation (Figure 8):

“His program dealt with the fundamental properties of protoplasma as affected by ions. He used as a model the Fundulus whose eggs develop equally well in distilled water and/or sea water. Loeb was surprised to find that on adding to distilled water as much sodium chloride as contained in sea water the eggs could not develop, in other words the sodium chloride is toxic and it was evident that the other salt found in sea water must somehow overcome this toxicity. The announcement of this fact was received with genuine astonishment” [1].

He found that the addition of all sorts of salts with bivalent or trivalent cations in the right proportion could more or less completely remove the toxicity due to salts with monovalent cations. He spoke of this as antagonistic salt action and called solutions as sea water, in which the toxicity is suppressed by the admixture of salt in the proper proportions, as physiologically balance solution [1].

In order to have antagonistic salt action toxic salts must be present in sufficient concentration to produce injurious effects and these injurious effects must be overcome by other salts which have a protective action [1].

Clinical applications of Loeb’s equations

Loeb’s equations are a dissipated heredity since they can still help in finding a rationale for understanding the effects of hyperkalemia, hyperkalemia with acidosis, hypocalcemia, hypocalcemia with alkalosis, and hypocalcemia with hypomagnesaemia [16] [17].

It should be noticed that all experiments were performed in the whole animal, as we learn [18]from his 1916 book The Organism as a Whole (Figure 9).

Acknowledgements

We wish to express heartfelt thanks to the people of the Archives of the Stazione Zoologica Anton Dohrn of Naples for continuous and expert assistance. They are capable, aware of their mission, work with enthusiasm and team spirit and keep the documents for posterity.

Introduction

The cultural movement that launched the Scientific Revolution of the 17^th century matured in the following century into what has been dubbed the Enlightenment or Age of Reason, a period of major achievements that for practical purposes can be divided into two stages. The first stage during which the new concepts and methodologies of the Scientific Revolution were developed and disseminated; and the second stage when they were tested, studied, refined, expanded and applied. The dominant figures of the first stage were born just before the end or during the 17^thcentury and were the founders who introduced measurement, mathematics and physics into scientific methodology (Galileo, Descartes, Newton, Harvey); whilst the second stage was led by a new generation which fueled by increased literacy, easier access to knowledge and facilitated exchange of ideas (journals, pamphlets, books, salons and academies) generated the intellectual forces of the 18^th century that would set in motion the power of enlightened reasoning applied to scientific methodology, which in turn would herald the coming of the Early Modern Age of the 19^th century (Figure 1). Whereas the transformative changes of the Enlightenment affected every level of society (social, financial, political, industrial, etc) it was in the sciences that its major impact was most evident. As a result, science became established as a branch of learning, with an exerted effort by universities to establish and expand their departments of the new and emerging scientific disciplines (astronomy, physics, mathematics, chemistry, etc). The three areas of medicine impacted by these transformative changes were in the development of physiology and pathology and the nascent attempts at launching chemistry [1] [2] [3].

The principal progress in Enlightenment physiology was in the rise of experimental physiology and reliance on mechanical explanations to interpret the generated data. The work of René Descartes (1596-1650) and Isaac Newton (1642-1687) were the basis of an increasingly convoluted mechanical philosophy that evolved from its simpler beginnings in the previous century laid by Giovanni Borelli (1608-1679), his colleague Marcello Malpighi (1628-1694), and his student Lorenzo Bellini (1643-1704) [1] [2]. A Scotish physician, Archibald Pitcairne (1652-1713) played a central role in the integration and elaboration of these new concepts into medicine that has been dubbed “Newtonian medicine” [2] [4] [5]. During a stay at Cambridge in 1692, Pitcairne was exposed to Newton who gave him a copy of his “De natura acidorum” in which he discusses the short range attractive forces of particles in solution, which Pitcairne went on to elaborate on how they applied to normal and abnormal physiology [4] [6]. Having established that the greater part of the body was fluid this new school of physiologists (Archibald Pitcairne, Robert Boyle, George Cheyne) reasoned that the normal and abnormal functions of the body could be explained by changes in the quantity, texture, flow and velocity of various bodily fluids, especially that of blood and glandular secretions [6]. The principles that emerged reached their apogee in the 1708 publication of “Account of Animal Secretion” by another Scotsman James Keill (1673-1719), who considered blood “a simple fluid in which a series of compounds of various shapes and magnitudes are endowed with different degrees of attractive forces” [7] [8] [9]. Familiar with the works of iatromathematicians as well as the metabolic balance studies of Santorio Sanctorius (1561-1636) that he translated into English, Keill was one of the first to work out the ratio of fluid to solid parts of the body through studies of tissue desiccation. He then delved into their broader implications in the context of the Harveian circulation of the blood by estimating the force of the heart, the pressure of the blood and the velocity of blood flow [7] [8] [9] [10]. In the absence of measured data, the efforts of Keill and others at determining the physical forces that defined the circulation were inaccurate and overestimated them rather grossly [11] [12]. The further study, quantification and elucidation of fluid mechanics and the actual strength of the physical forces governing them owes much to a handful of unique individuals who shaped the events that laid the groundwork for subsequent scholars and scientists to explore hemodynamics. One of the most celebrated figures to achieve that end was Stephen Hales (1677-1761).

Stephen Hales – the man

A clergyman by profession Hales was very much a scientific minded man of his times (Figure 2). His studies in the physiology of the circulation and the vascular system have been considered to be secondary in importance only to those made by William Harvey (1578-1657) [11] [13]. It has been said that Harvey demonstrated the logical necessity of the circulation, but it was Hales who provided its rigorous demonstration through his analysis of the hydrodynamics of the vascular system [14]. It has been said also that in animal physiology Hales took “the most important step after Harvey and Malpighi in elucidating the theory of circulation”. His contributions to physiology have been acknowledged by Michael Foster (1836-1907) and by John Fulton (1889-1960) who characterized him as “the most able physiologist of the eighteenth century” [2] [15]. In addition, Hales made significant contributions to respiratory chemistry that would stimulate the discoveries of Joseph Priestley (1733-1804) and Antoine Lavoisier (1743-1794), both of whom acknowledge his contributions in their publications, as does Daniel Bernoulli (1700-1782), who actually recommended to his students the reading and study of Hales’ Haemastaticks [12]. That such scientific work would be performed by a country parson deserves explanation. Although by no means on the level of the great clinical physiologists of the time who interpreted their studies in the context of body function, Hales was essentially a basic experimental physiologist at a transitional time in medical knowledge evolution when physiology was emerging from descriptive anatomy (Figure 1). As a pure physiologist his concern was not with medicine of which he knew little but that of refining the methods of experimental animal physiology to which he introduced the accuracy of measurement and the precision of mathematics. The calculations and contributions to hemodynamic of his predecessors, Richard Lower (1631-1791) and Lorenzo Bellini, notwithstanding, neither had the vaguest idea about the actual force of the blood pressure that had not been measured until Hales’ studies. It was his experiments which provided the data that would be completed by Bernoulli [16] [17] [18] [19].

Born in Bekesbourne, Kent in 1677, Hales was admitted to Benet’s College (now Corpus Christi) in Cambridge University in 1696 at the age of 18. He was elected a fellow of his college in 1702 and admitted as a fellow in residence the following year. It is there that he studied religion and delved into the sciences over the next 6 years until 1709, when he was appointed perpetual curate of Teddington, Middlesex (now part of Greater London), where he moved, worked and lived until his death in 1761. At his own request, he was buried under the tower of the Teddington chapel that he had added from his own personal funds [19] [20] [21]. His damaged tombstone found in the church porch was replaced in 1911 by a tablet reproducing his epitaph now placed on the west porch beneath the tower [13] [21] [22] [23].

Stephen Hales – the scientist

Whereas Hales begun his experimental studies while a resident fellow at Corpus Christi, his interest in science did not end with his departure from Cambridge. Actually he did most of his published scientific work in the fields of Teddington surrounding his curacy. Endowed by an unusually creative and inquisitive mind he occupied himself between his clerical duties with experiments that covered a wide range of the emerging scientific disciplines of the time, including the physiology of plants, the chemical constitution of air, reflex action, and, above all, his celebrated experiments on arterial and venous pressures in warm-blooded animals [20] [24][25] [26] [27] [28] [29]. He was early recognized as a leading investigator and elected to the Royal Society in 1717, at a time that Isaac Newton was its president. Shortly after his election he read his first paper to the Royal Society on the effect of the sun on the transpiration of plants. For his subsequent contributions he received the Copley Medal of the Royal Society in 1739, and was appointed one of the foreign members of the French Académie Royale des Sciences in 1753. In 1751, he was appointed Clerk of the Closet to the Princess of Wales, the mother of George III, who after his death put up a monument to his memory in Westminster Abbey (Figure 3) [20] [21] [22].

Hale’s foundation in the sciences was rooted during his years at Cambridge, in the heady atmosphere left by William Harvey and Isaac Newton. A principal contributor to his scientific interests was William Stukeley (1687-1765), who entered Benet’s College in 1703 to study medicine, became a close friend of his senior Hales and stimulated his interest in biology [7] [30]. Another contributor to Hales scientific education was John Vigani (1650-1712), an Italian scientist who became the first professor of chemistry at Cambridge in 1703 [20] [21]. Hales and Stukeley attended his lectures and watched his chemical demonstrations in the laboratory of Isaac Newton. Perhaps a greater intellectual influence on Hales was that of James Keill who by the late 1690s had started lecturing at Cambridge as well as at Oxford [6] [20]. It was around this time (about 1706) that Hales, together with Stuckeley carried out his first circulation experiments on dogs, but it was in Teddington that in or about 1714 he took up his studies in earnest this time on horses, dogs and does that would make him famous [20] [21] [31]. While the university taught him science, Stukeley stimulated his interest in biology, and Keill shaped his physiological thinking it was his own intellectual drive and revived scientific interest after settling in Teddington that formed the basis of Hales’ contributions to science.

Hales was slow to publish his studies. It was not until 1727 at the age of 40 that he issued the first volume of his now classic Statical Essays, the Vegetable Staticks, and six years later that he published the second volume of Statical Essays, which he titled Haemastaticks [20] [21] [31]. Published in 1733, the Haemastaticks is not a continuation of his studies in plant physiology published 6 years earlier. In fact, it is a report of his earlier studies of the early 1710s in the pastures of Teddington. Nor is it a book as much as it is a diary or laboratory notebook detailing his experimental studies, appended by his interpretation of their results and the questions raised by each experiment that prompted his subsequent experiment [32]. The published report was considered a model of rigorous research and clear exposition that resembled the work and writings of William Harvey, and their two books (the De Motu Cordis of Harvey and the Haemastaticks of Hales) were said to be “fitly regarded as a kind of principia for the physiology student.” [11].

The Haemastaticks opens with an account of Hales’s most dramatic experiment, a bold and bloody one on a 14 years old mare. Unfortunately, the design of this first recorded study has been miscommunicated as that of measuring the blood pressure in the carotid artery, and the importance of the results of the full experiment publicized as being limited only to that of measuring the blood pressure. Whereas Hales did measure carotid artery and jugular vein pressures that was on another 10-12 years old mare that he records as his third experiment. It is this third experiment that was illustrated as part of an advertising campaign for an industrial company, now out of business, which in the 1960s manufactured transducers, the Statham Medical Instruments, Inc. of Oxnard, California. The original figure clearly labeled as Experiment III (Figure 4) has come to be reproduced without its identifying footnote and often passed on as that of the first measurement of blood pressure. In fact Hale’s first classic experiment of measuring blood pressure was performed on an older live mare tied on her back on which after ligating one of her femoral arteries he inserted a brass cannula to which was fixed a glass tube nine feet high (Figure 4). When he untied the femoral artery ligature, the blood rose to a height of more than eight feet. He then detached the glass tube from its brass connection at intervals while measuring the quantity of blood to flow out and recording the resulting serial changes in blood pressure during exsanguination (Figure 5). His third experiment is publicized because he now measured arterial and venous pressure in the carotid artery and jugular vein. Actually, he had already established the “force of the blood” in his first experiment, his choice of the neck vessels was made because he wanted to cannulate the heart of the mare in order to make a wax cast of the intra-cardiac volume that would allow him to estimate cardiac output. In addition to horses, Hales studied the hemodynamics of the circulation in a number of other animals, including an ox, a sheep, a fallow doe, and several dogs in order to study the comparative physiology of the heart in different sized animals [20] [21] [31] [32].

Hales’ direct determination of the systolic pressure for the first time caused widespread interest and comment. His studies are significant not only because of the pressures which he recorded but because of his secondary observations as in the first experiment that on continuous withdrawal of blood the systolic pressure remained nearly constant until almost a third of the total volume of blood had been removed (Figure 5). He was thus led to postulate the existence of a compensatory mechanism for the constriction of peripheral vessels in order to maintain arterial pressure, which he explored further by perfusing exsanguinated animals with solutions of various temperature and varying composition to determine and record the changes in blood pressure caused by the constriction and relaxation of the peripheral vasculature [17] [19] [31] [32].

Stephen Hales – renal physiologist

In Haemastaticks Hales also describes his attempts to study renal perfusion. Essentially, after killing a dog by “washing his blood out” with warm water, and while the animal was kept warm, he placed a brass tube in the aorta above the renal arteries and gradually raised the “pressure of water equal to the force of the arterial blood which had been washed out in killing the dog, yet none of the warm water passed thro’ the kidnies into the ureters and bladder” [32]. Not an unexpected finding in the dead kidneys of a deceased animal, which in some ways replicates the earlier studies of Berengario da Carpi (1460-1530) and Marcello Malpighi to perfuse dead kidneys[1].

The Haemastaticks includes another renal issue to which Hales turned his attention in the late 1720s, a prevalent problem which had long challenged the resources of the medical profession: the painful affliction of kidney and bladder stones or “distemper of the stone” [20]. Early in 1727, while the Vegetable Staticks was still in press, he obtained human calculus specimens from his friend the surgeon John Ranby (1703-1773) and the then president of the Royal Society Hans Sloane (1660-1753). On distilling the stones Hales noted a much greater proportion of “air” than he had obtained from any other substance. Since various chemical agents were known to release this “strongly attracting, inelastic air,” he thought it possible to find a solvent to dissolve the calculi and obviate the painful operation of being “cut for the stone.” He carried out a number of studies and published their results in 1733 as the second part of his Haemastaticks [32] [33]. His continued attempts to find a useful solvent failed. These studies are noteworthy chiefly for his success in perfusing the bladder of dogs with various solutions and for his invention of a surgical forceps, which Ranby and other surgeons promptly used with success to remove stones from the urethra. In retrospect, where the first part of the Haemastaticks is a classic in experimental physiology, the second part on “Stones in the Kidnies and Bladder” is relatively naive and literally cluttered with bizarre experiments and simplistic conclusions. Ironically, it was for this largely inferior work on human calculi – not for his remarkable experiments on plants and animals – that Hales was awarded the Royal Society’s Copley Medal in 1739 [20] [21] [31].

An interesting sequel of his work on stones was his involvement in the case of Joanna Stepehens’ secret recipe for dissolving stones. He was appointed a trustee of the Parliamentary committee appointed to examine the effectiveness of the remedy, upon whose recommendation Joanna Stephens was paid £ 5000.00 in March 1740 to publish her recipe [20] [32] [33] [34].

Stephen Hales – philanthropist, social reformer and public servant

With the publication of Haemastaticks, Hales career in experimental animal physiology came to an end. He had been criticized for vivisection of animals amongst others by his neighbor since 1718 Alexander Pope (1688-1744) and a clerical colleague, Thomas Twining (1734-1802) [20] [21]. Pope who became a friend of Hales was horrified by his experiments that he describes as “barbaric” and reports him as “so worthy and good man, only I am sorry he has his hands so much imbued in blood”. Twinning in his poem The Boat, describing his travel down the Thames, relates his passage through Teddington as,

Green Teddington’s serene retreat

For Philosophic studies meet,

Where the good Pastor Stephen Hales

Weighed moisture in a pair of scales,

To lingering death put Mares and Dogs,

And stripped the Skins from living Frogs,

Nature, he loved, her Works intent

To search or sometimes to torment

From 1733 to the end of his life Hales devoted himself to applying his scientific knowledge, technical skills, and creative aptitudes to alleviating human problems, both medical and social[35]. Noteworthy in this regard is his work in the 1740s with ventilators whose use in mines, jails, granaries and ships he vigorously promoted, thereby establishing one of the first principles of preventive medicine [36]. An accomplishment well reflected in the definition of ventilators by Samuel Johnson (1709-1784) in his 1755 Dictionary of the English Language as, “an instrument contrived by Dr. Hales to supply closed spaces with fresh air.

At age 70 Hales was chosen by the Royal College of Physicians to preach the annual Croonian Sermon. For his sermon titled “The Wisdom and Goodness of God in the Formation of Man” he chose verses 11 and 12 from Job chapter 10: “Thou hast closed me with skin and flesh, and hast fenced me with bones and sinews. Thou hast granted me life and favour, and thy visitation hath preserved my spirit.” [37]. Verse 11 he had quoted with some modification in Haemastaticks (p. 160) to justify his studies in elucidating God’s creation: “Thou hast not only fenced me with Bones and Sinews, but hast also effectually secured the vital Fluid, in such strongly wrought Channels, as are Proof against its most lively and vigorous Sallies, when either agitated by the different Passions, or by strong or brisk Actions of the Body.”

Conclusion

For his scientific contributions to the to the circulation of blood, the flow of sap in plants and to the chemistry of respiration, Stephen Hales has been considered one of the most creative British scientists of the 18^th century. Francis Darwin (1848-1825), son of Charles Darwin, dubbed him “the father of physiology” [13].

Lost among the many contributions of Hales is his statement in the Introduction to Haemastaticks that “the healthy State of the Animal principally consists in the maintaining of a due Equilibrium between body solids and fluids”. In fact, by his own definition of “staticks”, borrowed from the 1614 De Medicina Statica of Santorio Sanctorius, Hales meant a state of “functional equilibrium”. A concept that he goes on to elaborate in Haemastaticks (page 109) [32], “The right healthy State of the Blood must consist in a due Equilibrium between these active Principles, so as not to have them too much depressed and fixed on the one hand, which might tend to an acid Acrimony, nor too much raised and exalted on the other hand, which makes it tend to an alkaline Acrimony.” The clearing of these excesses from the blood he ascribes to their clearance in the urine. Clearly insightful and prescient statements on the constancy of the internal environment, which would be promulgated in 1845 by Claude Bernard (1813-1878) as that of the “milieu intérieur”.