Panorama

VOL. 21 / N ÚM. 2 / A BRIL-J UNIO 2002

INMUNOLOGÍA, 2002; PP 115-118

In Memoriam: César Milstein (1927-2002)

A. GONZÁLEZ FERNÁNDEZ, A. K ARPAS*

Facultad de Ciencias. Universidad de Vigo. Pontevedra. Spain. *Department of Haematology.
University of Cambridge. MCR Center. Cambridge. United Kingdom

l Dr. César Milstein, uno de los más doctorado en Cambridge, Inglaterra, volvió a su

E grandes científicos de los últimos

siglos, falleció en Cambridge,
Inglaterra, el domingo 24 de mar-
zo de 2002 a la edad de 74 años. Su
nombre será recordado por su más famosa contri-
bución a la ciencia, la técnica de generación de los
anticuerpos monoclonales, pero aquéllos que lo
patria natal en 1961, que dejaría dos años después
obligado por la situación política argentina, para

conocimos personalmente, no olvidaremos nun-

ca a ese gran hombre humilde en cuerpo peque-
ño, a esa mente brillante, a ese gran maestro.
La técnica que César describió en colaboración
con el hoy también fallecido Georges Köhler,
publicada en Nature en 1975, les valió nueve años
más tarde el reconocimiento internacional con el
Premio Nobel de Medicina y Fisiología. Los anti-
cuerpos monoclonales han revolucionado los
campos de la ciencia, sobre todo en biomedicina,
y constituyen hoy una pieza indispensable en los
laboratorios para el diagnóstico, para la investiga-
ción e incluso para terapia (prevención de recha-
zo en trasplantes, tratamiento antitumoral, etc.).
Hoy la industria biotecnológica de los anticuer-
pos monoclonales mueve billones de dólares en
todo el mundo. La técnica no fue patentada en su
día por el instituto donde trabajaban César y
Georges, aunque sus autores no dudaron del
potencial de la técnica y de su interés comercial.
La biografía de César Milstein comienza en
1927 en Bahía Blanca, su ciudad natal argentina.
Se graduó y doctoró en Química en la Universidad
de Buenos Aires bajo la supervisión del profesor
Stoppani realizando estudios cinéticos en la enzi-
ma aldehído deshidrogenasa. Tras realizar otro

115
IN MEMORIAM: CÉSAR MILSTEIN
volver a Cambridge, con su esposa Celia, también
científica. Allí César trabajó en el Medical Research
Council, hasta el último momento. Seis días antes
de su muerte, enviaría el que fuera su último artí-
culo y falleció por fallo cardiaco después de toda
una vida dedicada a la ciencia.
Aunque César ha sido conocido por la técnica
de obtención de anticuerpos monoclonales, su
producción científica fue amplísima, con artícu-
los de extraordinaria calidad, y pioneros en
muchos campos, que le valieron el reconocimien-
to de la comunidad científica mundial, otorgán-
dole los más prestigiosos premios internacionales.
Fue todo un honor para la Universidad de Vigo, y
sobre todo para mí, que César aceptara la distin-
ción de Doctor Honoris Causa que la Universidad
le otorgó en el año 1999. Este acto de amistad nun-
ca podré olvidarlo, habida cuenta que había
renunciado a dicha distinción por parte de múlti-
ples universidades de todo el mundo; ni tampoco
los días que pasaron, él y su inseparable esposa
Celia, disfrutando del paisaje y gastronomía
gallegas.
César Milstein, a pesar de su brillantez como
científico, era muy diferente a otros científicos de
hoy en día metidos en la vorágine competitiva de
la publicación fácil y rápida, y sólo aceptaba cali-
dad e ideas innovadoras. César era una persona
paciente, que escuchaba, que te apoyaba en los
momentos difíciles, y que siempre tenía tiempo
para acudir en el momento que más lo necesita-
bas. Fue un gran maestro, que abrió sus puertas a
estudiantes de todos los lugares del mundo, y en
los últimos años a muchos españoles.
CÉSAR MILSTEIN: A SOMEWHAT PERSO-
NAL REFLECTION BY A. KARPAS
It would not be an exaggeration to describe
César Milstein's contribution among the most
important discoveries ever made in biological
science and medicine. The development of a
method to produce monoclonal antibodies rein-
vented the field of immunology. The ability to
produce monoclonal antibodies at will in the test
tube and in unlimited quantities, to any sort of
antigen whether an interesting chemical, infec-
tious micro organism, cancer or normal cells
opened numerous new and unforeseen avenues
for research. Many of the avenues had medical
implications. Not surprisingly, in 1984 César was
awarded the Nobel Prize, shared with Georges
Köhler and Niels Jerne; and according to a mem-
ber of the Nobel Committee he received the lar-
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VOL. 21 NÚM. 2 / 2002
Conocí a César, como le gustaba que le llama-
ran, hace ya 13 años, cuando aceptó que una estu-
diante inexperta predoctoral fuera a su laborato-
rio a aprender técnicas durante 4 meses.
Posteriormente, tras finalizar mi doctorado en
España, volvió a aceptarme en su grupo por un
periodo de cuatro años, y nuestra amistad ha con-
tinuado hasta el final. En mi recuerdo quedarán
imágenes de ese tertuliano afable, amigo de la coci-
na y del buen vino, su corazón cansado, su fuerte
acento argentino al hablar en inglés, sus paseos por
el río Cam en su barca o con su adorable perro
“Paco”, sus ricas paellas “colesterol free”, y su
humildad en el vestir y en el sentir.
El legado que deja César será imposible de olvi-
dar, y su muerte se lleva no sólo a uno de los más
grandes científicos, sino para muchos que lo cono-
cimos, a un amigo y a una gran persona.
CORRESPONDENCIA:
A. González Fernández
Facultad de Ciencias. Universidad de Vigo.
Lagoas Marcosende s/n.
36200 Vigo. Pontevedra.
Tel: 986-812625
Fax: 986-812556
e-mail: africa@uvigo.es
gest number of nominations from the distingui-
shed Nobel panel of selected scientists from
around the world.
However, the climb to the top was not an easy
one. César was born on 8 October 1927 in a pro-
vincial Argentina town as the second son to his
schoolteacher mother and his father who had
emigrated alone to Argentina from the Ukraine at
the age of 14. His parents saw to it that their 3
sons got a University education. César studied
chemistry at the University of Buenos Aires and
did a PhD in the same University working on the
active site in enzymes. In 1958 he won a British
Council research scholarship to the Biochemistry
Department of Cambridge and worked with Fred
Sanger (who was awarded his first Nobel Prize in
December 1958). Having collected a second
PhD, he returned to Buenos Aires in the hope of
contributing to Argentinean science. However,
INMUNOLOGÍA
obstructed by political interference he returned
to Cambridge at the invitation of Fred Sanger
who had by that time joined Max Perutz in the
newly formed MRC Laboratory of Molecular
Biology.
Following César's return to Cambridge he
started to work on antibodies and within a few
years he became an internationally acknowled-
ged leader in the field. In 1966 he published a
Nature paper with Sydney Brenner about the ori-
gin of antibody variation proposing that this
numerous variability results from mutations in
the genes of antibodies. He was particularly inte-
rested in the genetic mechanisms by which
humans or animals produce millions of different
antibodies (from which the immune system
selects those that bind to antigen), and also in the
mechanisms by which the binding affinity of
antibodies is improved on re-exposure to anti-
gen.
One of the ways he chose to tackle this ques-
tion was by using murine myeloma cells which
are the malignant proliferation of the antibody-
producing white blood cells. At that stage there
were no tissue culture facilities in the MRC buil-
ding, and César had no experience of tissue cul-
ture. He was allocated by the MRC a small win-
dowless basement store room as his tissue cultu-
re suite.
When I joined the Cambridge University
Department of Haematology in 1969 also located
in the MRC building, I was given a spacious virus
and tissue culture laboratory to study and grow
cells from leukaemia patients next to César's.
Naturally we met shortly after my arrival and on
a daily basis for years to come, and with my pre-
vious experience with cell culture I quickly beca-
me César's "cell doctor". By this time Richard
Cotton had joined César on a post doctoral
fellowship to try and fuse mouse myeloma cells
with the rat myeloma cells in order to study the
antibody production by the hybrid cells. At that
time the only agent known to fuse cells was inac-
tivated Sendai virus. I supplied this for his stu-
dies until a chemical agent replaced it in 1976. In
1973 César published, together with Richard
Cotton, a paper in Nature about the "Fusion of
Two Immunoglobulin Producing Myeloma
Cells". In fact it was the first antibody producing
hybridoma but it was created by two malignant
cells which readily grew in the laboratory and the
specificity of the antibodies it secreted was not
known.
Cotton then decided to return to Australia and
César began looking for a new postdoctoral resear-
cher to take forward the cell fusion project.
Georges Köhler had just completed his PhD at
the Basel Institut of Immunology and was attrac -
ted to the project. He joined César's group and
started to learn about cell culture in order to
A. GONZÁLEZ FERNÁNDEZ Y A. KARPAS
build on the groundwork by Cotton and
Milstein. Within two years Köhler and Milstein
published their seminal Nature paper demonstra-
ting that the fusion of the mouse myeloma cells
with a normal mouse lymphocytes, derived from
a mouse immunised against sheep red blood
cells, produced an immortal fused hybrid cell
(hybridoma) that was capable of synthesising
monoclonal antibodies against sheep red blood
cells in unlimited quantities. This 1975 paper not
only indicated that the method was likely capable
of producing monoclonal antibodies against any
agent recognised as foreign by the immune sys-
tem, but that monoclonal antibodies themselves
were likely to have important medical as well as
commercial implications. Although César's grea-
test talent was in innovative basic research he
immediately realised the financial potential of
monoclonal antibodies and lost no time in sug-
gesting to the MRC that his laboratory invention
should be patented.
Unfortunately this suggestion was dismissed,
due to short-sightedness in the National
Research and Development Corporation (NRDC)
which had a monopoly over MRC inventions,
leading to an enormous loss of potential royalties
from what has now become a multi-billion
pound industry. The loss did not escape the noti-
ce of the Prime Minister, Margaret Thatcher who
apparently made the point on greeting Sir James
Gowen who (then the head of the MRC) whene-
ver she met him, with "you lost us the monoclo-
nal patent".
Within a few years a very large number of
laboratories around the world had started to pro-
duce monoclonal antibodies to an ever-increa-
sing number of targets. The availability of mono-
clonal antibodies revolutionised both basic and
clinical research. For example, it enabled the first
purification of interferon, which was also done in
Cesar's laboratory by David Secher who had been
his research student. Monoclonal antibodies were
used to enable an accurate diagnosis of different
leukaemias and are used routinely in every medi-
cal centre to measure the levels of many proteins
in blood. When the antibodies are labelled with
radioactive chemicals they can be used to detect
and localise cancer tissue while an increasing
number of antibodies are used as 'magic bullets'
to destroy the malignant tissue of cancer
patients.
The 1970s were a golden era for César's re-
search and for those who followed his footsteps.
In 1972 he also published a paper in Nature about
the molecular mechanism and the process invol-
ved in the secretion of antibodies. This re-search
topic was subsequently followed by Gunter
Blobel who was crowned two years ago by a
Nobel Prize for a research topic that in which
Cesar was a pioneer. Due to his inspiration and
117
IN MEMORIAM: CÉSAR MILSTEIN
support, two other MRC scientists, Greg Winter
and Michael Neuberger made further groundbre-
aking discoveries in the development of new met-
hods to produce humanised and finally human
monoclonal antibodies. As a result Cambridge
can claim all the important discoveries and deve-
lopment in the monoclonal antibody field.
In spite of his official retirement in 1995 César
continued to be an active researcher. In July 2000
the MRC organised a Conference in London to
celebrate the 25th anniversary for the discovery
of the method to produce monoclonal antibo-
dies. In this conference not only scientists took
part but also politicians who knew of his impor-
tant contribution to science in general and
British medical science in particular.
César's interests were not confined to rese-
arch, he also followed the world news on a daily
basis and held opinions on important events. He
was also interested in numerous facets of the arts
(often going to the theatre and concerts in
London) and was an excellent cook. César was
also a man with great sensitivity to the human
right and justice. He advocated for peace and
compromise in national conflicts and was also
proud and keen about his family Jewish heritage.
In spite of the large number of international pri-
zes that showered upon him, César remained the
same modest and intellectually generous person
that I first met in 1969. He remembered my early
help with his work and invited me to take part in
the Nobel celebrations in Stockholm.
Over twenty five years ago he discovered that
he probably inherited his mother's vascular genes
118
VOL. 21 NÚM. 2 / 2002
who died at the age of 70 from a heart attack (his
father lived to 93) and resorted to a strict diet and
endless walks. When more serious cardiac pro-
blems developed he was looked after by the exce-
llent Cardiologists at Papworth Hospital, one of
whom told him that he felt that his major contri-
bution to science was keeping César alive and
walking. The admiration of his doctors was reci-
procated by César who was full of praise for their
efforts.
He has been very happily married to Celia for
nearly fifty years. Celia was also a research scien-
tist for many years and was the one who saw to it
that he never missed his doctor's appointments
and arranged for extra ones when she felt that he
needed to be seen earlier then expected. His
death robbed us of one of the best-loved and
most important scientists of the past century.
CORRESPONDENCE:
Abraham Karpas
Departament of Hematology
Universiti of Cambridge
MRC Centre, Hills Road
Cambridge CB2 2QH
United Kingdom
Tel.: 0044 1223 336823
Fax: 0044 1223 214788
e-mail: Karpasa@hotmail.com