Gérard Orth: From Viral to Human Genes Underlying Warts

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Vol.:(0123456789)
Journal of Clinical Immunology (2024) 44:106
https://doi.org/10.1007/s10875-024-01704-x
OBITUARY
Gérard Orth: From Viral toHuman Genes Underlying Warts
Jean‑LaurentCasanova1,2,3,4,5· EmmanuelleJouanguy1,2,3
Received: 30 March 2024 / Accepted: 8 April 2024
© The Author(s) 2024
Gérard Orth was born in 1936 and died in 2023. He was
picky and prickly. He was sharp and scholarly. He was stern
and serious. We loved him, even when he scolded us for
forgetting a footnote to an abstract for a communication at
a small workshop in a tiny town in the middle of nowhere
in the 1960s. Detail was everything to him, but he was also
unique in his global vision, which enabled him to make bio-
logical and medical breakthroughs in rabbits and humans,
but also to discover both viral and host determinants of
health and disease.
At the time of his death, Gérard Orth was Emeritus Pro-
fessor at the Institut Pasteur (where he worked from 1979
to 2003) and Emeritus Director of Research at the Centre
National de la Recherche Scientifique (CNRS, between 1966
and 2001). He was elected to the French Veterinary Acad-
emy in 2003 and the French Academy of Sciences in 2004.
Gérard worked at the Institut Gustave Roussy (IGR) in Ville-
juif from 1961 to 1979, initially in the “Laboratory of Bio-
chemistry and Enzymology” of Claude Paoletti, and then,
from 1975 onwards, in his own “Laboratory of Viral Etiolo-
gies of Human Cancers”. François Gros eventually invited
him to join the Institut Pasteur, where he founded and led
the “Papillomavirus Unit” from 1980 until his retirement in
2003. This laboratory was affiliated to the Institut National
de la Santé Et de la Recherche Médicale (INSERM). Gérard
Orth also served as Head of the Department of Virology at
the Institut Pasteur on two occasions, between 1991 and
1996 and between 2001 and 2003.
Gérard was born to a Protestant family from Alsace. Like
many Alsatians, he was a French patriot. On one occasion,
on arriving for dinner, the first thing he once told us, with a
certain excitement, was that he had finally understood how
Joseph Meister had been able to receive Louis Pasteur’s
experimental vaccine against rabies in July 1885, despite
living in Alsace during the short period between the Franco-
Prussian War of 1870 and World War I in which it was a
German province. Gérard’s detective work revealed that
Meister’s father had retained his French citizenship. That
made his day. And this was typical of Gérard’s conversation,
and of his life.
Gérard’s parents were born in Alsace, but they moved to
Paris briefly, subsequently settling in Saint Ouen l’Aumône,
a small town in Ile-de-France separated from the city of
Pontoise by the Oise River, where there was a small Protes-
tant community. His father worked as a manager in the agri-
food industry, while his mother was a housewife. Gérard was
born in Paris, 12 years after his parents’ marriage, and was
an only child. He later recalled that his Alsatian and Protes-
tant education instilled in him a “sense of duty, responsibil-
ity, and respect for others”.
Between 1946 and 1953, Gérard attended middle and
high school at the Lycée Jean-Claude Chabanne in Pon-
toise. This school was named after a member of the Resist-
ance from Pontoise who was murdered by the Nazis in 1942.
Jacques Dupâquier (1922–2010) was the only teacher at the
school he admired; he would later become an eminent histo-
rian, elected to the French Academy of Moral and Political
Sciences. Gérard also took piano lessons with the famous
composer Maurice Schwaab (1888–1953), who resided in
Pontoise. Gérard was not gifted enough to entertain any
thoughts of a musical career, but his talents were sufficient
for him to play the harmonium at the Protestant church in
Pontoise on Sundays. He obtained his Baccalaureate in 1953.
Gérard had considerable admiration for the civilizing and
humanitarian mission of the French Empire and, at one point
envisaged working in the upper echelons of administration
* Jean-Laurent Casanova
casanova@rockefeller.edu
1 St. Giles Laboratory ofHuman Genetics ofInfectious
Diseases, Rockefeller Branch, The Rockefeller University,
NewYork, NY10065, USA
2 Laboratory ofHuman Genetics ofInfectious Diseases,
Necker Branch, INSERM, Necker Hospital forSick Children,
75015Paris, France
3 Paris Cité University, Imagine Institute, 75015Paris, France
4 Department ofPediatrics, Necker Hospital forSick Children,
75015Paris, France
5 Howard Hughes Medical Institute, NewYork, NY, USA

Journal of Clinical Immunology (2024) 44:106 106 Page 2 of 11
in the French colonies. His parents opposed this plan, which,
indeed, did not seem timely in 1953. So, rather than prepar-
ing for the entry examination for the Ecole Nationale de la
France d’Outre-Mer (the National School for French Over-
seas Territories), he instead entered a preparatory school for
veterinary training. However, tormented adolescent that he
was, his chief reasons for going to veterinary school were
retaliation and provocation. He hated animals and secretly
hoped his parents would refuse this plan. He later admitted
that this was “an aberration for him and his parents”. He
suffered two years of intense study at the Lycée Marcelin
Berthelot in Saint Maur des Fossés. Marcelin Berthelot was
a nineteenth century French chemist and polymath. Gérard
then attended the national veterinary school at Maisons-
Alfort near Paris between 1955 and 1959 (Fig.1A).
Gérard had only a few friends among his classmates at
Maisons-Alfort, one of the most important of whom was
Jean-Charles Friedmann, to whom he owed his admiration
for Charles de Gaulle and unreserved support for the Gen-
eral’s actions after his return to power. Gérard recalled that
“Charles de Gaulle was a mentor for me. He instilled in
me "a certain idea of France" the roots of which I found in
his writings. I experienced the death of Charles de Gaulle
on November 9, 1970 as the loss of a loved one. I went to
Colombey-les-deux-Eglises to attend the General’s funeral.
I witnessed, by the side of the road, in the midst of thousands
of the faithful, including the actor Michel Simon and the ski
champion Marielle Goitschel, the departure of the armored
vehicle carrying the coffin of the General from La Boisserie
towards the church of Colombey. How can we forget the
great distress that marked the faces of the small number of
faithful, including André Malraux and Romain Gary, who
were the last to pay tribute to the General before he left La
Boisserie?”.
In 1958, Gérard had attended Charles de Gaulle’s Place
de la République speech establishing the 5th Republic, at
which political opponents voiced concerns about the “fascist
inclinations” of the man who had led the French resistance
against the Nazis — such is the nature of French politics.
Indeed, Gérard was a Gaullist, at odds with the mainstream
French scientific community, which consisted essentially of
supporters of various shades of communism and socialism,
among whom social democrats were the rare reasonable peo-
ple in the mad house. He did not really belong.
In 1957, Pierre Goret (1907–1994) welcomed Gérard
to his laboratory for the preparation of his Doctorate in
Fig. 1 A 1959 promotion of the
Veterinary School at Maisons-
Alfort (Gérard Orth is indicated
by the red cross). B 1959–1960
promotion of the Microbiology
cours at Pasteur Institute
(Gérard Orth is indicated by the
red arrow)
A
B

Journal of Clinical Immunology (2024) 44:106 Page 3 of 11 106
Veterinary Medicine (DVM), which he obtained in 1961.
He later recalled that “this status was abolished in May
1968, because it was assimilated to slavery!”. Pierre Goret,
who held the chair of contagious diseases of the Veterinary
School in Maisons-Alfort, played an essential role in his
career. Goret was a highly talented teacher and orator. As
a tutor, he was benevolent and understanding of Gérard’s
moods. With the assistance of Charles Pilet, Pierre Goret
got Gérard involved in his work on an interesting topic, the
then enigmatic relationship between the viruses responsible
for measles in humans, distemper in dogs, and rinderpest
in cattle.
Gérard’s work focused on the antigenic and immunogenic
relationships between the distemper and rinderpest viruses,
with the rabbit as a model. This period marks the start of his
interest and expertise in rabbit biology, which later made a
major contribution to his studies of papillomaviruses. The
experimental approach used, based on the inoculation of
rabbits with blood or tissue homogenates, with daily tem-
perature readings and autopsies, was the one that Edmond
Nocard (the discoverer of Nocardia and one of the famous
veterinary surgeons in the Pasteur saga), the founder of the
laboratory, had implemented in 1888.
This study led to his first publication as coauthor of a
paper published in 1960 in the Annales de l’Institut Pasteur
[1]. His DVM thesis, which he defended in 1961, was enti-
tled "Sur les relations antigéniques et immunogéniques du
virus de la maladie de Carré et du virus de la peste bovine.
Recherches expérimentales chez le lapin" (On the antigenic
and immunogenic relationships of the distemper and rin-
derpest viruses. Experimental studies in the rabbit) (Fig.2).
His thesis was rewarded with a prize in the form of a medal
representing Henry Bouley (1814–1885), a figurehead of
veterinary medicine in the nineteenth century. This inspired
Gérard, who had collected stamps as a child, to collect med-
als, particularly those devoted to Louis Pasteur and his dis-
ciples or emulates.
Goret triggered Gérard’s vocation for science and acted
as his mentor from 1957 to 1961. It is to Goret that Gérard
owed his attraction to microbiology and research. Goret
taught him that research must have ambitious objectives and
that its success is dependent on hard work and availability,
including during weekends. However, Gérard rapidly came
to understand that it also required a certain amount of talent
and a lot of luck. From then on, his path lay clear before him:
“I will be a researcher”. Pierre Goret was also the key to his
recruitment as an agent on a scientific contract at the Institut
National de la Recherche Agronomique (INRA) during his
last year at Maisons-Alfort (1959).
Gérard was proud to be a veterinarian. He was proud that
veterinarians had understood and supported Pasteur when
physicians were opposed to him [2]. He was all too aware
that physicians in academia were all too often more inter-
ested in power plays than in the search for truth — espe-
cially in France, where so many become addicted to “medi-
cal power”, combatting “mandarins” in their youth, only
Fig. 2. 1961, Doctorate in Veterinary Medicine. Left to right: Cover page of the Doctorate in Veterinary Medicine (DVM), Acknowledgments to
Profs. Goret and Brion, concluding remarks of his DVM

Journal of Clinical Immunology (2024) 44:106 106 Page 4 of 11
to become even worse “mandarins” as their age and power
increased. He wondered how Antoine Lavoisier, who had
pushed for the election of physicians to the French Academy
of Science, would consider his decision with hindsight. The
likes of François Magendie and Claude Bernard had become
a rarity. Gérard liked to say that veterinarians were a hum-
bler and more serious breed. He admired many, and perhaps
especially Gaston Ramon (1886–1963), who had discovered
the principle of vaccination with anatoxin.
Gérard attended the Microbiology (1960) and Immunology
(1960) courses at the Institut Pasteur in Paris. The “Grand
Cours de Microbiologie”, now defunct, was the heir to the
“Cours de Microbie Technique” created by Pasteur in 1889
(Fig.1B). Its primary purpose was to teach systematic micro-
biology. However, it also represented an opportunity, then
unique in France, to discover the nascent molecular micro-
biology developed at the Institut Pasteur by André Lwoff,
Jacques Monod, François Jacob, and Elie Wollman. Gérard
had bought and read with great interest "The sexuality of bac-
teria", a book published by E. Wollman and F. Jacob (prefaced
by A. Lwoff) in 1959, before reading Jacques Monod’s thesis
on the diauxic growth of bacteria. He then “understood the
growing importance of molecular microbiology relative to
traditional systematic microbiology”.
Gérard would have to wait another 20 years to join
the Institut Pasteur. In 1961, he met Claude Paoletti
(1928–1994), who became his second mentor during his
two years of military service at IGR in Villejuif, where he
served as army midshipman to the naval animal facility.
Paoletti headed the “Laboratory of Biochemistry and Enzy-
mology”, which focused on the biochemistry of DNA and
DNAses. He soon got Gérard involved in a new project on
the biological properties of polyoma virus DNA. He encour-
aged Gérard to collaborate with Pierre Lépine at the Institut
Pasteur. A collaboration was also established with Pascu
Atanasiu in Lépine’s department, for the performance of tis-
sue culture experiments that would not have been possible
in Villejuif. This was Gérard’s second interaction with the
Institut Pasteur.
Pascu Atanasiu (1913–1995) welcomed Gérard to the
Virology Department (Service des Virus) located in the Darré
Building in 1961. Gérard then discovered another facet of
research. Under the auspices of Pierre Lépine, Head of Depart-
ment since 1941, the writing of grant applications and activity
reports was not a matter of major concern, contrary to what he
had previously learnt with Paoletti. At the time, Pierre Lépine
(1901–1989) personified French virology. In 1941 he was
appointed head of a group of viral research departments, after
the management of the Institut Pasteur decided to unify the
various laboratories dealing with viruses into a single depart-
ment. Lépine improved laboratory techniques by installing two
high-speed centrifuges in his department, together with the first
electron microscope in France, jointly funded by the CNRS.
Lépine participated in the drawing up of plans for the
Darré Pavilion, the Service des Virus, at Institut Pasteur,
funded by a donation from Mrs. Darré, the widow of the
former chief physician of the Pasteur Hospital. Lépine’s
fame was due largely to his invention of the French vaccine
against poliomyelitis. In 1957, Salk and Lépine published
the results of their work a few weeks apart [3–5]. The two
vaccines differed in the strains used. The “Lépine vaccine”,
published in 1954 [6], was produced from selected weakly
neurovirulent poliovirus strains grown in the kidney cells of
African monkeys not infected with the SV40 virus, which
is oncogenic. Lépine prevented any risk of infection by per-
forming a double inactivation of the virus, first with forma-
lin, and then with beta-propiolactone. Vaccination with the
Lépine vaccine was made compulsory in France in 1964, and
the rapid generalization of poliomyelitis vaccination practi-
cally eliminated infantile paralysis in France.
Gérard was particularly fond of a very “French” anecdote
about Lépine, who had married Marie-Madeleine Dollfus
(1906–1990) in 1926. He also had a well-known, long-stand-
ing relationship with Christiane Petersen (1911–2008), with
whom he had a daughter and two sons. Petersen had tried,
without success, to make the Lépine’s divorce a condition
for recognition of his paternity. She was behind the publi-
cation of a book by X, “On achève bien les cobayes”, the
hero of which was inspired by P. Lépine and paints a very
unflattering portrait. The sale of this book was banned until
the death of P. Lépine in 1989, when both Marie-Madeleine
Lépine and Christiane Petersen (both under the name of
Madame Lépine!) announced his death in Le Figaro!
The Darré Building housed various research and diag-
nostic laboratories (poliomyelitis, influenza, rabies, etc.), as
well as a rich library and communal laboratories for classical
virology (histology, electron microscopy, preparation of ster-
ile glassware). Unfortunately, the turning point in modern
virology — molecular approaches to studying the interaction
of viruses with their host cells — had not yet been reached.
In the absence of seminars, the primary opportunity for
interactions between members of the Virus Service was pro-
vided by attendance at the Virus Club, a restaurant located
in the Borrel Building adjacent to the Darré Building, at a
time when there was no cafeteria accessible to members of
other departments of the Institut Pasteur.
Gérard later recalled “how could I have imagined then that
I would become the head of the Virology Department in 1991
and that, on my initiative, the Salle Pierre Lépine (the library of
the Darré Building) would be inaugurated in 1992, decorated
with a Pierre Lépine medal designed by R. Pépin? This event
was commemorated by the production of a medal representing
Pierre Lépine on one side and the Darré Building on the other.
And how could I have imagined that both the Darré and Borrel
Buildings were destined for demolition in 2024 to make way for
a vector-borne infectious diseases research center!”.

Journal of Clinical Immunology (2024) 44:106 Page 5 of 11 106
Pascu Atanasiu (1913–1995) devoted himself mainly
to the study of the rabies virus. His laboratory contained
a few trainees and technicians with complementary skills.
He had recently become interested in tumors induced by the
polyoma virus, following a stay with Karl Habel at the NIH.
Atanasiu, himself of Romanian origin, had been a friend
of Constantin Brancusi (1867–1957), the famous Romanian
sculptor. Brancusi had made him the executor of his will,
with the mission of transferring his workshop at Impasse
Ronsin to the National Museum of Modern Art.
Gérard’s arrival in his laboratory coincided with the end
of the fight between Atanasiu and Alexandre and Natalia
Istrati, painters of Romanian origin, whom Brancusi had
hosted at Impasse Ronsin, and who opposed the transfer
of the studio. Gérard recalled that “I had the privilege
of attending the inauguration of the reconstitution of the
studio featuring major works by the artist at the Palais
de Tokyo in 1962, shortly after my arrival at the Pasteur
Institute.” Atanasiu introduced Gérard to techniques for
studying the polyoma virus exvivo and invivo, and the
collaboration between the Gustave Roussy and Pasteur
institutes resulted in several publications, including
Gérard’s first article (written with the help of Karl Habel)
in an international journal [7].
After his military service, Gérard continued his training
in genetics and biochemistry at the Faculty of Sciences (Bio-
chimie Générale (1963), Biochimie Approfondie (1963) and
Génétique Générale (1964) certificates) and completed his
work on the polyoma virus in the context of a scheduled
return to INRA. He presented this work at a competitive
examination at the end of 1962 for the post of research assis-
tant at the newly created Veterinary Research Department
of the IGR. He won first place and was predicted a brilliant
career as a civil servant at INRA. Paoletti then offered him
a place as a PhD student studying the effects of ultraviolet
irradiation on the biological properties of polyoma virus
DNA in his laboratory at the IGR.
Paoletti and Orth became close friends. Gérard belonged
to the “Pao Gang” and was responsible for establishing the
“Claude Paoletti Prize” shortly after Paoletti’s death. One of
the authors (JLC) first entered Gérard’s office in the Virol-
ogy Department of the Institut Pasteur in 1997 as one of
the first laureates of this prize. He encountered mountains
of printed papers of unequal heights, separated by a narrow
gorge leading to the desk, behind which Gérard was seated.
The light was dim. At the time, Gérard was chairing the
Claude Paoletti Prize Committee and this meeting took place
in preparation for the award ceremony.
Gérard had the reputation of having read everything. He
had certainly read our papers. The laureate was bombarded
with incisive questions that went well beyond his papers
and attested to both Gérard’s elephantine memory and his
unsatiable curiosity. He did not feel that he had passed the
test until Gérard asked him if his father was of Corsican
descent, like Claude Paoletti. He will never know whether
his surname contributed to his selection as the laureate.
Coming back to Paoletti and Orth, Paoletti suggested that
Gérard should do his PhD studies in collaboration with the
Institut Pasteur. He suggested that Gérard submit this pro-
ject to Jacques Monod. The resulting meeting with Monod
played a key role in Gérard’s career, leading him to resign
from INRA in 1963. Monod received Gérard at the Institut
Pasteur in November 1963. As Gérard recalls, “Monod had
not shown any obvious interest in the subject that C. Paoletti
had suggested to me. He had told me about a recent arti-
cle by Stanfield Rogers demonstrating that an L-arginase
encoded by the viral genome was induced in cutaneous pap-
illomas caused by the Shope papilloma virus in wild cot-
tontail and, in experimental conditions, in domestic rabbits
[8]. The possible malignant transformation of warts that
this DNA virus induces under natural (cottontail rabbits) or
experimental (domestic rabbits) conditions made the Shope
virus the first paradigm for the study of viral carcinogenesis
in mammals, thanks to the work of Peyton Rous and his col-
leagues. Unlike cottontail rabbit papillomas, domestic rab-
bit papillomas induced in experimental conditions display
a repression of viral replication. Why did the induction of a
cutaneous wart (and cancer) require a viral gene encoding
an enzyme the cellular counterpart of which was involved in
the last stage of hepatic ureogenesis?”.
Jacques Monod invited Gérard to present an analytical
seminar on this article in the presence of four future Nobel
Prize winners: François Jacob, Salvatore Luria, André
Lwoff, and Jacques Monod! Jacques Monod judged his sem-
inar “excellent” and concluded: “You have to work on that”.
This did not fail to impress Paoletti, who then suggested that
Gérard should study arginase at Villejuif. Gérard recalled
that “the fact that a student of Jacques Monod, Jean-Pierre
Changeux — who was then writing his famous thesis on
the allosteric properties of L-threonine deaminase — was
going to join the laboratory as one of the army of research-
ers working on this problem, was a determinant factor in
my decision to take the plunge. And this, despite the dif-
ficulties of studying an enzyme so far removed from nucle-
ases and despite the fact that papillomas were induced by
a virus that did not grow exvivo. The only source of the
Shope virus was warts taken from living cottontail rabbits
(Sylvilagus floridanus) from the banks of the Mississippi,
as domestic rabbit papillomas only exceptionally produced
virus! After my meeting with J. Monod, my scientific life was
centered on cottontails or domestic rabbits for about ten
years.” Gérard also recalled that “The collection of 34 rab-
bit statues in glass, crystal, porcelain or bronze that I have
since amassed testifies to this! The faithful and affectionate
friendship that binds us, Jean-Pierre and myself, also dates
from this period”.

Journal of Clinical Immunology (2024) 44:106 106 Page 6 of 11
Jean-Pierre Changeux, the eminent Institut Pasteur bio-
chemist and neurobiologist, was Gérard’s only true friend
from his own generation. Both were mentored or influenced
by Lwoff, Monod, and Jacob. They shared an admiration for
great minds and groundbreaking discoveries off the beaten
track. They were elitist, placing scientific truth above all
else, and they favored a Malthusian scientific effort. Moreo-
ver, despite differences in their political opinions, they spoke
their minds freely, abhorring the politically correct discourse
that progressively gained momentum in Western academia.
Finally, both were patriots.
The results that Gérard obtained in collaboration with
Françoise Vielle-Breitburd, under the supervision of Jean-
Pierre Changeux, clearly demonstrated the cellular origin
of the arginase of papillomas. Using partially purified
enzyme preparations, they showed that the papilloma and
liver arginases had similar kinetic and immunological
properties, indicating that the genetic information for the
tumor enzyme was probably carried by the rabbit genome
[9]. These results, in opposition to those of Rogers, would
have allowed Gérard to defend his thesis within a reasonable
time frame. However, he did not defend his PhD, despite
an agreement between Jacques Monod and Claude Paoletti.
Jacques Monod had agreed to be a member of the PhD jury
(Fig.3). Gérard then recalled “But I then decided to have
myself as my only mentor, throughout my career, often at
my own cost. This would not have been possible without the
understanding, patience, and friendship of Claude Paoletti”.
In an attempt to reproduce the induction they had
observed invitro, Gérard and his collaborators obtained
domestic rabbit keratinocytes with ultrastructural character-
istics attesting to their epidermal origin [10]. The infection
of cultures of these cells with the Shope virus did not lead
to arginase induction. Only a modest increase in arginase
activity was observed in papilloma cell cultures. Further col-
laborative work with Vielle-Breitburd led to the determina-
tion of the properties and subunit structure of highly purified
rabbit liver arginase [11–13].
Such work would not have been possible without a long
and fruitful collaboration with Odile Croissant, head of the
electron microscopy laboratory of the Virus Department
of the Institut Pasteur. One of the striking observations
to emerge from this work was their demonstration of the
induction of DNA synthesis in keratinizing keratinocytes
from domestic rabbit warts, which produce virus only excep-
tionally, whereas no such DNA synthesis was observed in
papillomas induced with dimethyl-benzanthracene. Rashad
and Evans had reported similar observations [14]. One of
Fig. 3 Letter of Claude Paoletti to Jacques Monod in 1969 about the PhD defense of Gérard Orth and the response of Jacques Monod (Pasteur
Institute, (MON.COR.12))

Journal of Clinical Immunology (2024) 44:106 Page 7 of 11 106
the first applications of insitu hybridization to the study of
viruses enabled Gérard and his coworkers to demonstrate
that this DNA synthesis corresponded to cellular DNA, in
the absence of viral DNA replication [15].
Gérard’s “non-defense” of his PhD thesis since 1966 led
the CNRS to question his right to membership of this organi-
zation. As a result, Gérard, in a highly disturbed emotional
state, devoted all his energy to another attempt at writing
this thesis in 1971 and 1972, at home, in Sceaux. Gérard
recalled that “at the beginning of 1972, I submitted the man-
uscript, entitled ‘Analysis of viral genome expression during
abortive or productive infection of the epidermal cell by the
Shope papilloma virus’ to C. Paoletti, my PhD supervisor.
The manuscript included two dedications, one referring to
Louis Pasteur (‘If joy is in success, virtue is in effort’) and
the other to André Lwoff (‘Despite the harsh disciplines it
imposes, scientific research, as everyone knows, is part of
playful activity’), in homage to two scientists who served as
a reference in my moments of doubt. C. Paoletti had sug-
gested minor modifications, and François Gros, the reviewer,
and André Lwoff, member of the Jury accepted my manu-
script: ‘I, the undersigned, André Lwoff, Honorary Professor
at the Faculty of Sciences declare that I accept the thesis
presented by Gérard Orth’, ‘I, the undersigned, Prof. F. Gros
declare having examined Mr. Orth’s PhD thesis and having
considered it acceptable for an imminent defense. F. Gros’
(April 17 1972)”. However, Gérard recalled that “After years
of depression, I decided to turn the page and not defend this
PhD, instead focusing on the study of the wart virus, hop-
ing to find variations in the sequence of the viral genome
that could account for clinical variations (localization of
the lesion, outcome, epidemiology …)” [16].
Indeed, Gérard had his ups and downs. One sentence he
once whispered to us, not without hesitation, more than a
decade after our first encounter, was “Je ne m’aime pas”.
He didn’t mean “I do not love myself”. He felt that no-one
should love themselves, because pride is one of the seven
deadly sins. What he really meant is “I do not like myself”.
At the crepuscule of his life, he had both remorse and
regrets.
Nevertheless, Gérard could be both tactful and gracious.
It was only after years of dinners at the Dôme, a seafood
restaurant at Montparnasse, that he confessed to us that he
hated seafood. After that, we crossed the Boulevard Mont-
parnasse and dined at the Rotonde, his favorite place, or
sometimes at the Select or the Coupole. He enjoyed these
brasseries, where great writers and artists had gathered
before World War II.
Having decided to focus on the wart virus, Gérard turned
to human studies in 1973. His epiphany occurred in 1972,
when he first heard of epidermodysplasia verruciformis in
the article by Jablonska, S. Jakubowicz, K., Dabrowski, J.
“Epidermodysplasia verruciformis as a model in studies
on the role of papovaviruses in oncogenesis” published
in Cancer Research in March 1972 [17]. This article
highlighted the role of host genetic factors and immune
factors (cellular immunity disorders possibly secondary
to the chronicity of infection). Jablonska etal. then
hypothesized that the papovavirus particles observed in
benign lesions might play a role in the initiation of cell
transformation specific to epidermodysplasia verruciformis.
She also suggested that genetic factors were responsible for
the chronicity of infection.
Another decisive moment came on December 15–16,
1975 (Medical aspects of human wart virus infection).
Proceedings of a Fondation Mérieux seminar held in Lyon
on December 15–16, 1975). This was the occasion of the
first meeting of Gérard Orth with Stefania Jablonska. With
hindsight, Gérard would say that Goret, Paoletti, Monod,
Changeux, and Jablonska were the five people who counted
the most in his scientific life.
Indeed, his true love was epidermodysplasia
verruciformis [18–21]. Gérard was a great admirer of
Stefania Jablonska, the head of the dermatology department
in Warsaw, Poland. This was the Poland from before the fall
of the Iron Curtain. Using hetero-inoculation, Jablonska had
shown that epidermodysplasia verruciformis was triggered
by a virus [22]. She and Gérard teamed up to identify and
characterize this virus [23]. Although he had heard that
Jablonska was not unfriendly to the communist regime,
Gérard admired her, perhaps because of her extraordinary
scientific achievements in such dire conditions, and perhaps
because of her Jewish origins and decision to stay in Poland.
He would not say more on this topic. He was particularly
proud to have received the 1985 Robert Koch Prize with
Jablonska, for which he gave his acceptance speech in Berlin
in German. He was also elected a foreign member of the
Polish Academy of Sciences in 1997.
Gérard was truly encyclopedic, and this could be utterly
exhausting for anyone in his company. Mr Teste, a character
created by Paul Valéry, would say that “silliness is not my
strength”. It would be fair to say that concision was not
Gérard’s strength. He could not provide a short answer
to any question, in any circumstances. His e-mails, in
particular, were Tolstoian, even though he had very little
taste for anything Russian. His writing style was very
formal, “vieille France” as the French would say. The last
of the Mohicans.
Accordingly, his papers and his talks were extraordinarily
long, complicated, obscure, and therefore difficult to
follow. There was always an exception to an exception to
an exception. He did not believe that there were any rules in
biology. He was right, of course, to be a radical nominalist,
because biology is not made for typologists, intellectuals
who flourish in physics but tend to encumber biology and
embarrass themselves by their perpetual search for the “laws

Journal of Clinical Immunology (2024) 44:106 106 Page 8 of 11
of nature”. However, this attitude was not didactic, to say the
least, and it certainly did not contribute to his popularity.
But Gérard never considered himself to be in a popularity
contest. Nobody understood the classification of human
papillomaviruses like him. Maybe that was the problem with
the classification that he helped to build.
Gérard recalled with a grin that he was called “mein
Bruder” by Harald Zur Hausen; they held joint laboratory
meetings for a time. Zur Hausen won the Nobel Prize for
the development of a vaccine against oncogenic mucosal
HPV, but it was Gérard who first showed that cutaneous
HPV infections could be oncogenic in epidermodysplasia
verruciformis patients [24], before the demonstration that
genital HPV infection can underlie cervical cancer. Gérard
tended to irritate his colleagues not only by always being
right, but also by making it clear to them that he was right.
However, this was not a question of pride. Instead, it attested
to an absolute and sometimes excessive or exclusive respect
for science.
Gérard was a giant in virology and a giant in immunology.
He pioneered the field of papillomaviruses, discovered an
entire genus of human papillomaviruses, the defective but
oncogenic beta HPV, which cause disease in rare patients
with epidermodysplasia verruciformis [16, 25–27]. As
if being an extraordinary virologist were not sufficient,
he discovered the first human genes underlying warts, in
patients with epidermodysplasia verruciformis [28–30].
Who else can say that they have discovered both a microbial
pathogen and the corresponding human genetic lesion?
Gérard Orth had the unique technical versatility to be able
to switch from viral identification to human linkage analysis,
from sequencing viral genes to sequencing human genes,
and the intelligence to understand that the microbe is merely
a trigger that reveals an underlying, pre-existing condition
of the host.
While the vast majority of microbiologists remained pris-
oners of Koch’s radical version of the germ theory, Gérard
knew that microbes cause disease only rarely, in individuals
in whom human genetic and immunological determinants of
disease operate. He therefore decided to discover why some
rare individuals develop flat warts and skin cancer triggered
by the weakly virulent, defective beta-HPV he had discov-
ered with Stefania Jablonska [16, 20].
The first time we heard the term “intrinsic immunity”, it
came out of his mouth [18, 31–33]. Twenty-five years ago,
he convinced us that epidermodysplasia verruciformis had
to be due to a derailment of keratinocytic intrinsic immunity.
At that time, keratinocytes had not even been considered as
a possible branch of host defense. This idea gained ground
when he found mutations underlying epidermodysplasia
verruciformis.
Indeed, in 2002, Gérard published the breakthrough dis-
covery that biallelic mutations of EVER1 or EVER2 underlie
a significant proportion of cases of epidermodysplasia ver-
ruciformis [29]. Luckily, the two genes are located in tan-
dem, accounting for the single linkage peak. This discovery
was the second elucidation of the molecular genetic basis
a known Mendelian infection, of which five were known
at the time [34, 35]. Nicolas Ramoz, the PhD student who
performed this work, defended his thesis at the Institut Pas-
teur, where it attracted little attention. One of us (JLC) was
a member of the jury. Gérard was forced to retire soon after
this breakthrough, whilst still in his prime, attesting to the
nonsensical and counterproductive rigidity of the employ-
ment rules in French academia.
Gérard was continually surprised and dismayed by the
decline of the scientific community of France and the
Institut Pasteur. He could not help wondering how Pasteur,
an institute as richly endowed as some of the wealthiest
American institutions, a unique feature in the European
research landscape, had produced so little since the late
1960s, and why even when it did produce results of interest,
it was often by accident. How could an institute with so
much money produce so little science? This was one of his
recurrent questions. The discovery of HIV was one of his
favorite examples. Gérard loved quoting François Jacob
allegedly saying during a meeting: “People say Montagnier
discovered a virus; I think a virus discovered Montagnier”.
Gérard was also particularly fond of another anecdote.
A colleague of his at Institut Pasteur had doubts about the
scientific quality of a younger French scientist because of
his many publications in prestigious journals. Gérard was
fond of Johan Sebastian Bach and had read (in German) the
essay about Bach written by his Alsatian compatriot Albert
Schweitzer (the physician, Nobel Prize winner, who had
spent his professional life in the tropical forest of Gabon,
was born in German-occupied Alsace, and was a relative
of Jean-Paul Sartre — who declined the Nobel Prize).
Distraught by the insanity of this concern, Gérard would say,
tongue in cheek: “My colleague would doubt Bach’s genius
because Bach composed a masterpiece almost every week”.
Gérard grew increasingly tired of having to tolerate the
mediocrity around him. He became misanthropic and was
further weakened by his myelodysplasia. In 2022, he was
unable to travel to Newport Beach to receive the Thomas
A. Waldmann Award for excellence in the field of human
inborn errors of immunity, which he so richly deserved, in
person from Sudhir Gupta. He gave his speech by video link,
and he looked exhausted. In previous years, Gérard not only
frequently came to visit our laboratory in Paris, but also
hopped on a plane to spend some time with us in New York.
When he retired in 2003, Gérard joined our laboratory
as a consultant. He even made us his “légataire universel”.
He gave us all his samples, contacts, patients, archives,
and, more importantly, all his thoughts. The CIB1 saga that
followed was particularly exciting [36]. After having found

Journal of Clinical Immunology (2024) 44:106 Page 9 of 11 106
mutations of T-cell genes in patients with an “atypical”
form of epidermodysplasia verruciformis, we finally found
mutations of a new gene in patients with a “typical” form
of epidermodysplasia verruciformis. These patients did not
suffer from other infections. Jill de Jong, in our laboratory,
connected the dots and found that CIB1 forms a multimer
with EVER1 and EVER2. Some of these patients were
even of particular importance to Gérard, including one
originally described by Wilhelm Lutz in Basel [37] and one
family from Algeria that Gérard had followed for decades.
Gérard was content — a rare state of mind for him.
We published nine papers together. Our next paper on
epidermodysplasia verruciformis will be dedicated to him.
Gérard died while working on a paper retracing his
career that he had promised for the Journal of Clinical
Immunology. We found only three successive versions of
a draft retracing the first two decades of his career on his
computer. Many of the quotes in this obituary were taken
from these documents, which also inspired this obituary.
Even after a glass of wine, or two (or even three), or
with a cigar, Gérard would only sparingly and timidly share
anecdotes about his private life. He loved the impressionists
and Hansi (Fig.4A). Hansi (1863–1951) was an Alsatian
illustrator and French patriot. He was particularly fond
of Pissarro (1930–1903), as many paintings of his are of
Pontoise and Saint Ouen l’Aumône, where Gérard grew
Fig. 4 Hansi and Pissarro paintings at Pontoise from 1867 to 1878. A Selection of 2 paintings from Hansi. B Selection of 6 paintings of Pissarro
on “L’usine de Pontoise”

Journal of Clinical Immunology (2024) 44:106 106 Page 10 of 11
up (Les bords de l’Oise près de Pontoise; Bords de l’Oise;
Usine à Saint-Ouen l’Aumône 1873. La crue de l’Oise; La
sucrerie au bord de l’Oise; Usine près de Pontoise; Le Quai
du Pothuis à Pontoise) (Fig.4B). These paintings opened a
window onto his youth.
Gérard never married and did not have children. This
was a source of regret to him. He bitterly regretted his
loneliness, which increased when his laboratory closed
and was mitigated only partially by his frequent conversa-
tions with Jean-Pierre Changeux, his work in our labora-
tory, and our dinners at the Rotonde. However, he had
no regrets about having devoted so much time to rabbits,
papillomaviruses, epidermodysplasia verruciformis, and
intrinsic immunity (Fig.5). He was also glad to have been
inspired by five extraordinary mentors and colleagues.
Gérard did not like himself, but we loved him. He will
be sorely missed.
Acknowledgements We thank the Service des Archives and the Photo
library of Pasteur Institute, l’Association des anciens élèves de Mai-
sons-Alfort, including Profs. Jean-Paul Mialot and Bernard Toma in
particular, and the archives of the veterinary school at Maisons-Alfort.
Author Contributions JLC wrote a first draft of the manuscript, and
EJ prepared all figures. Both authors edited and finalized the text and
figures together.
Data Availability No datasets were generated or analysed during the
current study.
Declarations
Competing Interests The authors declare no competing interests.
Open Access This article is licensed under a Creative Commons Attri-
bution 4.0 International License, which permits use, sharing, adapta-
tion, distribution and reproduction in any medium or format, as long
as you give appropriate credit to the original author(s) and the source,
provide a link to the Creative Commons licence, and indicate if changes
were made. The images or other third party material in this article are
included in the article’s Creative Commons licence, unless indicated
otherwise in a credit line to the material. If material is not included in
the article’s Creative Commons licence and your intended use is not
permitted by statutory regulation or exceeds the permitted use, you will
need to obtain permission directly from the copyright holder. To view a
copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Fig. 5 Top left: Around 1990, Gérard Orth and a researcher analyz-
ing an electrophoresis (photography of Béatrice de Cougny, Pasteur
Institute). Top right: Around 1990, Gérard Orth in his office. Bottom
left: In 2002, Gérard Orth attending a workshop on host genetics of
infectious diseases organized by Jean-Laurent Casanova at the Fonda-
tion des Treilles (Gérard Orth is indicated by the red cross). Bottom
Right: A portrait of Gérard Orth around 2010

Journal of Clinical Immunology (2024) 44:106 Page 11 of 11 106
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