Renal Unit, Guy's and St Thomas' Hospitals, Guy's, King's and St Thomas' Medical Schools, King's College, London, UK
Introduction
Much of medical history, especially that written by doctors or medical scientists rather than historians, centres on the role of talented and original individuals in determining the changing course of clinical practice, usually defined retrospectively as progress, although this is often far from the case. In contrast, the thesis of this article is that although Georg Haas (18861971) performed the first tentative fractionated dialyses in humans in 19241925 using collodion membranes and hirudin as anticoagulant [13], practical dialysis only became possible in the early 1940s as a result of the availability of two new substances. These substances were cellulose acetate (cellophane) membranes and tubing, and the new anticoagulant heparin. As with so many developments in medicine, dialysis was made possible by substances that were introduced with purposes unrelated to this area of medicine, and cellophane was developed from outside medicine altogether. Without these new materials, the successful pioneers of haemodialysis in the 1940s would have been as relatively powerless as their predecessors.
What was wrong with hirudin and collodion, the substances that made the first in vivo dialyses of blood possible? Actually, almost everything was unsatisfactory: hirudin, although (with difficulty) commercially available, usually had to be prepared fresh, was almost invariably toxic, and was completely unstandardized. Collodion tubing or sheets needed preparation immediately before use, were difficult to sterilize, were fragile, and were of variable porosity. In the face of these difficulties, Haas gave up clinical dialysis for a while in 1926. New materials were needed.
Heparin
The first description of heparin has been clouded in controversy, and has been much discussed. An anticoagulant phospholipid was described in an extract of liver in 1916 [4] by a second-year medical student, Jay Maclean (18901957; Figure 1) [58] who was working under the direction of the Professor of Pharmacology, Willam Henry Howell (18601945) at the Johns Hopkins Hospital in Baltimore. Maclean had been born in San Francisco, the son of a surgeon, who had died when Jay was only 4 years of age. He supported himself as a labourer before entering pre-medical studies in the University of California in 1914, and came to Johns Hopkins Hospital in 1915, with the aim of completing a research project, whilst working unpaid, in a relatively short time [5]. Howell suggested he study a number of thromboplastic (procoagulant) substances. Maclean did this, but said of one prepared from liver:
The hepatophosphatid on the other hand when purified by many precipitations from alcohol at 60°C had no thromboplastic effect, and in fact shows a marked power to inhibit coagulation. The anticoagulating action of this phosphatid is being studied and will be reported upon later ...
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Fig. 1. The discoverers of heparin. (a) Jay Maclean (18901957) as a young man and in later life (courtesy of The Alan Mason Chesney Medical Archives, Johns Hopkins University and the late Dr Conrad Lam). (b) James Henry Howell (18601945) as a young man (courtesy the Alan Mason Chesney Archives, Johns Hopkins University).
Howell initially seems not to have welcomed this discovery, perhaps because it disagreed with his theories of coagulation [68]; Maclean later recalled that he was an outsider in the laboratory [5], but both he and Howell [8] later referred to the other as their best friend. Clearly the relationship was a complex one, as was Howell's attitude to Maclean's data. Maclean left for Philadelphia in 1917, but stated later that he hoped to continue work there on the phospholipid he had discovered. In fact he did work there on cephalin, but on its procoagulant activity rather than on anticoagulants [9]. After a period with the American Army in France, he took his MD in 1919, and returned to the Hopkins, but he entered the surgical service under Halsted, since he wished to be ... a physiological surgeon rather than an anatomical one.
Meanwhile in 1918 [10] and 1920 [11] Howell published papers together with a retired paediatrician, L. Emmett Holt (18551924), who had replaced Maclean on the project; in these papers mention was made Maclean's contribution. In these papers the enduring name of heparin was first used for the new principle, because of its origin in the liver. Howell never again mentioned Maclean in print; he and Holt became renowned for their discovery, whilst Maclean's contribution to the project languished. In the following years Maclean had an unsatisfactory and obscure career, first as an instructor in clinical surgery in California (a post for which he appears to have had no talent and practised little or not at all), spent some poorly documented time in Paris and Germany, and then returned to New York in 1924, where he worked in the pathology department of Ewing at Cornell from 1927 to 1939. During this time he used heparin to anticoagulate dogs given either pneumonia or abdominal adhesions. He then occupied a post in experimental surgery at Columbus at Ohio State University, undertaking private practice also, using radiotherapy. At this time he published a further note on heparin [12], and for a long period planned a monograph on heparin; this was, however, never completed. He worked in administrative posts in Washington and Savannah, GA until his death in 1957. His role in the discovery of heparin was only noted publicly in 1945, and then after his death in 1957 [6].
William Henry Howell (18601945) was born in Baltimore, and like his colleague John Jacob Abel, he was a pupil of the noted physiologist Newell Martin at the Hopkins [8,13] (Figure 2). He graduated in 1884 with a doctoral thesis on blood coagulation, which remained a central interest for the remainder of his career; only 8 years later he was appointed professor of Physiology at his alma mater, and remained in this post throughout his career. Howell postulated that, as well as substances promoting coagulation (thromboplastins), the body must produce one or more natural anticoagulants. It was with this in mind that Howell set his student Maclean to work, with the surprising results that some phosphatids from liver were not procoagulant as Howell had anticipated, but anticoagulant. Maclean wrote much later that Howell permitted him to include these unexpected results only in the text of the paper, and not in its title, summary, or conclusions. Significantly also, Howell did not appear as co-author. Howell continued work in this direction, mentioning Maclean in his Harvey lectures of 1917, and in 1918 he published what became the classic paper naming heparin, together with Holt [10]; again in this paper, Maclean's work is credited. In a letter to Charles Best (see below) in 1940, Maclean wrote that Howell invited him to be a co-author of the now classic 1918 paper, but he (Maclean) declined because:
... I had participated to such a small extent in this later work and I did not feel entitled to the privilege offered ...
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Fig. 2. William Thalhimer (18861961). His newspaper obituary gives his age at his death on Sept 12th 1961 as 75 years, but the NY Academy of Medicine gives his birth date as 1884 in their records (courtesy of the National Library of Medicine, Washington, USA).
It appears in retrospect, in the light of both Maclean's letters to Best and his posthumous autobiographical account [6], that Howell was always willing to give him full credit both publicly and privately for his description or discovery of heparin; but that Maclean became progressively disillusioned by the fact that in the public arena only Howell (and Holt) received credit. This led to a sad campaign from 1940 onwards to establish his priority, which became almost an obsession. After his death, a plaque to Maclean was put in place at the Johns Hopkins in 1963:
In recognition of his major contribution to the discovery of heparin in 1916 as a second-year medical student in collaboration with Professor William H. Howell ...
Heparin is purified and identified
In 1918 and for the next few years Howell was still under the impression, as a result of Maclean's work, that the principle was a phosphatid, i.e. a phospholipid. During the next 10 years he worked almost alone on the purification from dog liver of what he continued, confusingly, to call simply heparin, eventually using aqueous rather than ether extraction, clearly indicating that it could not be a lipid. This was confirmed in 1925 when he demonstrated the absence of phosphorus in the molecule: by 1928 he had identified it as a sulphur-containing glycosaminoglycan [8], and most readily obtained from intestine rather than liver. The name heparin, however, was still employed, and has proved durable. However, these early preparations were crude and variable and of low potency, and thus unsatisfactory for the clinical application of heparin to the treatment and prophylaxis of thrombosis and embolism, major problems in surgery.
Early dialyses using heparin
Even so, a crude low-potency heparin became commercially available for experimental use as early as 1923 from the Baltimore company of Hynson, Westcott, and Dunning, and was used for dialysis in animals and even in humans. Heinrich Necheles (18971979) [14] had used hirudin to perform dialyses in uraemic dogs in the same year in Hamburg, Germany, employing prepared peritoneum (Gold-beater's skin) as a membrane [15]. Supported by the Rockefeller Foundation, he went to China to work in the physiology department of the Peking Union Medical College. Here news of the new anticoagulant, heparin, arrived, probably through Clarence Mills, a coagulation expert also working in Peking [14]. Necheles used it with his Chinese collaborator R. K. S. Lim mainly to extract substances of physiological interest from the blood plasma [15,17,18]a return to John Abel's original use of the technique in 1913. Meanwhile Leonard Rowntree (18831959), having left Abel's department at the Johns Hopkins after their pioneer work with Benjamin Turner on vividiffusion in 19121914, was now chief of medicine at the Mayo Clinic. In 1927 he became interested in the treatment of pulmonary embolism and turned again to his knowledge of the technique of vividiffusion to study the effect of heparin in an extracorporeal circuit in dogs, using a single collodion dialysing tube [1921]. Rowntree and his colleague Takuji Shionoya re-discovered the important effects of turbulence of blood in avoiding pooling and thrombosis, which Von Hess and McGuigan had noted a decade earlier [22], but they examined this phenomenon in much greater detail.
Also using the new anticoagulant, in 1928 Georg Haas started again and dialysed two patients on a 1.5 m2 dialyser [23], but still using collodion membranes. Although the patients improved the results were to Haas disappointing. The practical difficulties were too great, the clinical gain seemingly negligible, and opposition from his colleagues and peers formidable.
Standardization of heparin
For clinical use, a reliable standardized preparation of heparin was needed. Thus it was that teams involving biochemists and surgeons tackled the problem together. From the early 1930s, the co-discoverer of insulin, Charles Best (18991978) set out in the Connaught Laboratories in Toronto, Canada to purify and standardize pure heparin prepared by chemists Arthur Charles and David Scott in 19331934 [24]. They confirmedas Howell had indicatedthat it was more easily prepared from tissues other than liver, such as lung and especially intestine, and they purified and standardized it for clinical use. The clinical team was led by surgeon Gordon Murray (18941976) [25], one of three individuals who later developed a practical artificial kidney during the early 1940s. Murray and his colleagues were able to show that heparin could be used prophylactically against deep-vein thrombosisa major landmark in medicine. In parallel, haematologist Erik Jorpes and surgeon Clarence Crafoord conducted similar experiments in the Karolinska Institute in Stockholm.
Cellophane
Now, with heparin available, the remaining great technical problem of a suitable and robust dialysis membrane was solved. The membrane had to be sterilized easily, without damage to the material or alteration in its properties, and with long shelf lifeon both of which counts collodion performed badly. This problem was solved, outside medicine or even science, by the packaging industry.
The term cellulose, as the name for the major constituent of wood, related chemically to starch, was coined in 1839 by a committee of the Académie des Sciences in Paris [26] as ... a compound which fills the cells and which makes up the substance of the wood itself. This was one of a number of words ending in ... ose, including glucose, created by various committees of the Académie about this time. At about the same time, the explosive gun cotton (cellulose trinitrate) was synthesized and studied by the Frenchman H. Branconnot in 1833 and Jean-Jaques Pelouze in 1838, and particularly by Johann Freidrich Schönbein of Basel (17991868) in 1846 [27], whose work finally brought it to wide attention. Its explosive properties were its main attraction, and later it formed the main component of Alfred Nobel's dynamite [27]. However, dissolved in mixtures of alcohol and ether, cellulose trinitrate could be poured and evaporated, leaving a porous film. This was the collodion film used for photography in the wet collodion process described by William Scott Archer (18131857) in 1851. It was used as a surgical dressing during the nineteenth century, as well as being better than natural membranes such as peritoneum, reeds etc. for in vitro and in vivo dialysis, until the end of the 1920s. Cellulose nitrate remained also the medium for cinema film stock until the 1920s, despite problems with flammability and stability.
Cellulose itself was first purified from wood in 1885 by Charles F. Cross and Edward Bevan at the Jodrell Laboratory of the Royal Botanic Gardens at Kew in London [28]. The main early interest in the biology and chemistry of cellulose was naturally from the paper-making industry. Cellulose acetate was first synthesized about 1895 [28] and as early as 1910 this form of regenerated cellulose was available in sheet form from the Société Industrielle de Thaon in France, under the name of cellophane [28], and was widely used for food packing from about 1920 onwards. Fagette [29] reviews descriptions and studies of this material during the 1920s in detail. The raw cellulose was dissolved in sodium hydroxide (and in later processes mixed with carbon disulphide), then added to glacial acetic acid before being precipitated. The fact that cellulose would also dissolve in solutions of copper in ammonia (cuprammonia, Schweitzer's reagent) was already established by 1862 [28], although it was not exploited to make cellulose films for dialysis until the 1960s by the Bamberg company in Germany.
Cellulose acetate was rapidly perceived as having clear advantages over cellulose nitrate for dialysis. Cellophane was used for laboratory studies of dialysis in sheet form by Freda Wilson of the University of British Columbia in 1927 [30]; she showed how easy it was to sterilize this material, unlike the case with collodion. By then, in the late 1920s this versatile and cheap product was made into tubing for the manufacture of sausages by the Visking Company of Chicago. It was tough, did not burst under moderate pressures and even in its commercial form was relatively free of microscopic holes. Almost immediately this sausage skin was used in laboratory dialysis experiments by Andrus [31], and it proved to have excellent diffusion characteristics. During the 1930s many papers (reviewed by Fagette [29]) were published on the physical and dialysis characteristics of various forms of cellulose membranes, although it seems doubtful that the pioneers of dialysis in the 1940s were aware of any of these datacertainly none of them quoted any of the many papers, which had been published mostly in chemical and industrial journals.
Heparin and cellulose come together for dialysis in Thalhimer's laboratory
The newly purified and standardized heparin from Toronto had come to the notice of a New York haematologist working in the convalescent serum laboratory of the New York Public Health Institute, William Thalhimer (18861961) (Figure 2) [32]. Thalhimer played a pivotal role in the history of haemodialysis, but hitherto has received little or no attention from historians of nephrology.
Thalhimer had graduated from Johns Hopkins Hospital in 1908, where he was a pupil of Abel amongst others. He then became a non-clinical haematologist and worked in laboratories at the Mt Sinai Hospital in New York from 1911 to 1918, followed by 11 years at the Columbia Hospital in Milwaukee. In 1929 he moved to the Michael Reese Hospital in Chicago, before returning to his native New York in 1936 to work in the Public Health Research Institute. He remained there until 1944 and this was where he did his work on exchange transfusion and dialysis. Thereafter he worked in the Queens Blood Bank and in Grasslands Hospital, Valhalla, NY. Drukker [33] states (without giving a source) that Thalhimer saw a demonstration of Abel's dialyser when he was a medical student at the Johns Hopkins University, but this cannot be exact in view of his graduation date; perhaps this event took place later during a subsequent visit to Hopkins. Thalhimer visited Toronto in the early 1930s, and remained in contact with Best's team [24].
One of Thalhimer's main interests at this time was blood transfusion, for which he employed heparin as an anticoagulant [34]. He was intrigued also by the idea of exchange transfusion and its therapeutic potential, and he used heparin to allow exchange transfusion for alleviation of uraemia in nephrectomized dogs [35]. He then went on to construct an artificial kidney with cellulose tubing 2 cm wide and 30 cm long and an Abel-type kidney to dialyse dogs [36], using heparin as an anticoagulant. The dialyses lasted 35 h, and up to 1.5 g of urea could be removed.
Thalhimer's vital contribution to the evolution of haemodialysis was the realization that commercially available cellophane tubing could be used for in vivo dialysis:
... these preliminary experiments suggest the possible use in humans ... however this human application should not be made until further investigation, which is now under way in collaboration with professor C. H. Best ...
This fascinating note suggests that Gordon Murray may have got the idea of constructing a dialyser in 1940 in Toronto from discussions between Thalhimer and Best, and later Murray himself mentions Best alongside Abel and Thalhimer as having embarked on similar investigations [37]. The following year, joint work with Best, on plasmapheresis rather than dialysis, and in dogs rather than humans, was published [35].
However, we can see how knowledge of heparin was transferred one way, and of the cellulose tubing the other, between New York and Toronto. Thalhimer, in a footnote, says he was unaware of the work of Necheles and Haas until he was writing up his own data. He does not quote any of the laboratory work on in vitro dialysis using cellophane, his main emphasis being on the use of heparin: he notes only that he obtained his cellulose tubing from the Visking company. Why he did not pursue investigation of the artificial kidney further is unknown. He would certainly have known of Murray's work in Toronto on the artificial kidney begun in 1940, and regarded this as sufficient outcome. He retired from the serum laboratory in New York 1944, from consulting haematology in 1950, and he died in 1961.
Thus at last, with the availability of standardized pure heparin and cellophane tubing off the shelf, the scene was set for effective dialysis in humans. In retrospect one could predict that the 1940s would see the development of practical haemodialysis, and that it would probably evolve simultaneously in several different institutions and countries, given that the information and the technical resources were now widely and cheaply available. The only surprise is that this next development did not take place in the United States, as Europe was again plunged into war by the time the decade beganalthough Canada played its role.
All of the three pioneers of practical haemodialysis, Willem Kolff (b 1911), Nils Alwall (19061986), and Gordon Murray (18841972) were aware of Thalhimer's work on heparin and cellulose tubing only a year or two previously, and all three cite his papers. Murray, as we have seen, was intimately involved in the heparin story, and must have met Thalhimer personally during the 1930s. It is not so clear how and when Alwall became aware of cellophane and heparinhe mentions Thalhimer's work on cellophane in his early papers, but neither here nor in his historical surveys of dialysis does he say how he came by this knowledge. Presumably he knew of heparin from Jorpes' work at the Karolinska Institute in Stockholm. Kolff was told about cellophane by his mentor Professor R. Brinkman in Gronigen, who had himself built a multiple-tube cellophane dialyser for in vitro use [38], and he learned about heparin from Jorpes' work in Sweden [38]. Modestly, Kolff acknowledged the role of the introduction of these two vital materials in a retrospective article written in 1965 [39]:
Since I had both heparin and cellophane, all that remained was to build a dialyzer of sufficient capacity to make the application clinically worth while.
One million individuals world-wide now owe their lives to this technology, which was the result of new materials as much as of the men directly involved.
Note added in proof
Since submitting this paper my attention has been drawn to the paper: Martin RS, Colombi A. Christian Friedrich Schönbein (17991868): from the perilous explosive guncotton to the salutary dialysis membranes. Am J Nephrol. 1992; 12: 196198. This gives details of Schönbeins life and confirms that guncotton was, in fact, known before his patenting and publicizing of the compound. In addition, an important new paper on Jay Maclean and Cepharin has been published, based in his letters and manuscripts archived in Washington, DC: Marcum JA. The origin of the dispute over the discovery of heparin. J Hist Med Allied Sci 2000; 55: 3766.
Notes
Correspondence and offprint requests to: Emeritus Professor J. S. Cameron, Elm Bank, Melmerby, Penrith, Cumbria CA10 1HB, UK.
Bibliography and Notes