Practical haemodialysis began with cellophane and heparin: the

Nephrol Dial Transplant (2000) 15: 1086–1091
Nephrology
Dialysis
Transplantation
Historical Note
(Section Editor: J. S. Cameron)
Practical haemodialysis began with cellophane and heparin: the crucial
role of William Thalhimer (1884–1961)
J. Stewart Cameron
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 (1886–1971)
performed the first tentative fractionated dialyses in
humans in 1924–1925 using collodion membranes and
hirudin as anticoagulant [1–3], 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 anticoCorrespondence and offprint requests to: Emeritus Professor J. S.
Cameron, Elm Bank, Melmerby, Penrith, Cumbria CA10 1HB, UK.
agulant phospholipid was described in an extract of
liver in 1916 [4] by a second-year medical student, Jay
Maclean (1890–1957; Figure 1) [5–8] who was
working under the direction of the Professor of
Pharmacology, Willam Henry Howell (1860–1945) 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 premedical 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 …
Howell initially seems not to have welcomed this
discovery, perhaps because it disagreed with his theories of coagulation [6–8]; 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 (1855–1924), who had replaced Maclean
© 2000 European Renal Association–European Dialysis and Transplant Association
Haemodialysis: the role of William Thalhimer (1884–1961)
(a)
1087
(b)
Fig. 1. The discoverers of heparin. (a) Jay Maclean (1890–1957) 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 (1860–1945) as a young man
(courtesy the Alan Mason Chesney Archives, Johns Hopkins University).
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 (1860–1945) 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 …
It appears in retrospect, in the light of both
1088
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 sulphurcontaining 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 (1897–1979) [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 (1883–1959), having left Abel’s department
at the Johns Hopkins after their pioneer work with
J. S. Cameron
Benjamin Turner on vividiffusion in 1912–1914, 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 [19–21]. 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 (1899–1978) set out in the Connaught
Laboratories in Toronto, Canada to purify and standardize pure heparin prepared by chemists Arthur
Charles and David Scott in 1933–1934 [24]. They
confirmed—as Howell had indicated—that 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 (1894–1976) [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 thrombosis—
a 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 life—on 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
Haemodialysis: the role of William Thalhimer (1884–1961)
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 JeanJaques Pelouze in 1838, and particularly by Johann
Freidrich Schönbein of Basel (1799–1868) 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
(1813–1857) 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
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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 data—certainly 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 (1886–1961) ( 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
Fig. 2. William Thalhimer (1886–1961). 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).
1090
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 3–5 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
J. S. Cameron
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 began—although Canada played its
role.
All of the three pioneers of practical haemodialysis,
Willem Kolff (b 1911), Nils Alwall (1906–1986), and
Gordon Murray (1884–1972) 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 heparin—he 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 (1799–1868): from the perilous
explosive guncotton to the salutary dialysis membranes. Am J Nephrol. 1992; 12: 196–198. 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: 37–66.
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