a Arnold Martin Graffi died at his home in Berlin-Karow on January 30, 2006 at the age of 95 years. He was one of the last survivors of the distinguished group of scientists who, mainly in the post-war period of the twentieth century, profoundly shaped the field of experimental cancer research and therewith laid the foundations for the modern understanding of cancer and the subsequent development of molecular oncology. Graffi, who dedicated his career to diverse aspects of cancer research, ranks with the most brilliant scientists of the field including Karl Heinrich Bauer, Joseph Beard, Isaac Berenblum, Eric Boyland, Adolf Butenandt, Hermann Druckrey, Ludwik Gross, Antoine Lacassagne, Otto Mühlbock and Charles Oberling, to mention some of them.

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Arnold Graffi at around the age of 65 years

Graffi was born into a family of Transylvanian Germans in Bistritz (now Bistrita, Romania) on June 19, 1910. It was his father, a teacher, who made sure that Arnold obtained a humanistic education. After finishing the gymnasium in 1928, Arnold left his home country for Germany, where he stayed for the rest of his life.

Arnold Graffi studied at the universities of Marburg, Leipzig and Tübingen. The subject area that most strongly attracted the medical student was the study of cancer as taught by the pathologist Albert Dietrich in Tübingen. From 1935 to 1939, he was trained in gynecology under Georg August Wagner and in surgery under the renowned Ferdinand Sauerbruch at the Charité Medical School in Berlin. In 1940, he received his M.D. degree with a specialization in gynecology from the University of Berlin. Encouraged by his teachers, he soon entered the field of experimental medicine. Beginning in 1939, he embarked on a training tour in both academia and industry, which provided him with a far-ranging intellectual stimulus and an unusually high degree of skill in a wide field of medicine. Starting with microbiology at the State Institute of Experimental Therapy in Frankfurt headed by Richard Otto, he went on to pathology (University of Prague with Herwig Hamperl), to histology and tissue culture (University of Budapest with Tivadar Huzella), to biochemistry and hormone research (Main Laboratory of Schering AG Berlin with Karl Junkmann) and finally culminating in cell physiology (Kaiser Wilhelm Institute for Cell Physiology, Berlin, with the great Otto Warburg). In 1949, he qualified as a university lecturer in experimental pathology. Two years later he was appointed professor at Humboldt University in Berlin.

Already during his time at the Sauerbruch clinic, Graffi began to establish a research program of his own. His very first work, which was published in 1939 and 1940, proved to be a great success. Taking advantage of the fluorescent properties of the strong carcinogen benzo[a]pyrene, he investigated the subcellular distribution of this compound after painting it onto the skin of the backs of mice. The observed preferential accumulation of benzo[a]pyrene all over the mitochondria led him to propose that the development of cancer might be primarily caused by mutations of cytoplasmic organelles. The story came full circle when 25 years later the presumed mitochondrial DNA was actually discovered. Graffi immediately returned to his first love, and he and his associates were able to demonstrate a preferential reaction of mitochondrial DNA as compared to nuclear DNA with N-nitroso carcinogens in vivo. Later on, similar results have been obtained for a large variety of chemical carcinogens including benzo[a]pyrene. In the past several years, compelling evidence has been accumulated for an important role of mitochondria in cancer, apoptosis, and aging.

In 1948, Graffi moved to the place where he remained until his retirement. Based largely on his early work with carcinogens, Graffi was recruited by the director, the biophysicist Walter Friedrich, to a chair in the newly established Institute of Medicine and Biology at the German Academy of Sciences in Berlin-Buch in the former East Germany. Here, he became the founding director of experimental cancer research. The laboratory that he established soon became one of the outstanding schools of research in the field. He built it from the ground up to a staff size of about 80. As a charismatic mentor, he was able to produce a creative research environment. Over the years, Graffi held positions of increasing responsibility and was finally appointed director of the Institute of Cancer Research.

It is not possible to cover here the large body of Graffi’s achievements, only some of them can be mentioned in the following. Graffi is best known for his work on tumor-inducing viruses, notably the discovery in 1954 of the Graffi murine leukemia virus, one of the first known mammalian retroviruses. In 1951, Ludwik Gross had succeeded in proving the viral etiology of lymphatic leukemia in mice by cell-free transmission of a subcellular agent of the high-leukemic AK strain into neonatal C3H mice. Thereby stimulated, Graffi attempted to transmit cell-free extracts from various transplantable mouse sarcomas and carcinomas to newborn mice. He and his co-workers expected to induce similar tumors in the inoculated mice. To their surprise and in contrast to the situation with the Gross virus, however, the inoculated inbred or random-bred mice developed myeloid leukemia with a high frequency. Yet spontaneous occurrence of this type of leukemia was known to be very uncommon. A major part of these leukemias showed the characteristic appearance of chloroleukemias (a form of myeloid leukemia characterized by greenish discoloration of involved lymph nodes). Graffi and his associates also observed a spectrum of leukemic cell types after repeated animal passage of the viral agent, indicating that it might be a complex of several virus entities. In subsequent studies, other isolates of murine leukemia viruses were reported by Charlotte Friend, John Moloney, Frank Rauscher, and many others. These and various other retroviruses were instrumental for the future development of the concept of viral oncogenes and proto-oncogenes. Today, the Graffi virus is still an excellent model to study the mechanism of myeloid leukemia induction and to identify novel proto-oncogenes. More recent studies have shown that the Graffi virus is a complex of ecotropic retroviruses which do not contain oncogenic sequences, but rather deregulate genes because of proviral integrations. A subclone of this complex predominantly causes myeloid leukemias.

A second Graffi virus is the hamster polyoma virus. It was first isolated in 1967 from skin epitheliomas arising spontaneously in a Syrian hamster colony. Interestingly, inoculation of the virus into newborn hamsters from a separate colony induces lymphoma and leukemia. As its close relative, the mouse polyoma virus, the hamster counterpart has been subsequently studied as an interesting model of tumorigenesis in some more detail by other authors. Last but not least, Graffi succeeded just before his retirement in isolating a type D retrovirus from human cells. The origin of this virus, which was later molecularly cloned and found to be very similar to but distinct from certain simian AIDS viruses, remains to be determined.

In his golden 1950s, Graffi also essentially contributed to the knowledge of chemical carcinogenesis. He immediately saw its far-reaching consequences behind a minor observation. In original experiments, he used the two-stage methodology introduced by Berenblum for various detailed investigations including dose/response and structure/activity studies. He found that some polycyclic aromatic hydrocarbons (notably benz[a]anthracene) as well as urethane (ethyl carbamate), though themselves not carcinogenic for mouse skin, could act as pure initiators when subsequently promoted with croton oil. Later on he discovered N-nitrosomethylurea as one of the strongest carcinogens when topically applied to the skin of rodents. He also showed that after a single administration to newborn mice the same compound exhibits a strong leukemogenic effect. In addition to his own work, Graffi promoted excellent studies in his institute on various topics such as on the antigenic properties of tumors induced by murine retroviruses and by chemical or physical carcinogens, the mutagenic effect of N-nitroso carcinogens, and the mechanism of lysogeny as a model for viral oncology.

Another highlight of Graffi’s belle époque was the writing, together with Heinz Bielka, of the then influential book “Probleme der Experimentellen Krebsforschung” (Problems of Experimental Cancer Research). Its German version was first published in 1959 and was soon translated into French and Romanian.

Already in the early 1960s, Graffi proposed that since cancer might be caused by some alteration of genes, a treatment should be possible by modifying certain gene activities. In hindsight this was one of the first considerations of cancer gene therapy. In his late years, he started a more traditional project on experimental cancer therapy. He modified the known prodrug strategy by using an exogenous pH-dependent enzyme, which was administrated to tumor-bearing animals together with cleavable transport forms of cytostatic drugs. In the acid environment of the tumor, the enzyme became activated and was then able to cleave the prodrug under liberation of the active cytostatic drug. Some technical problems with the enzymes, however, prevented a wide employment of this method.

In acknowledgement of his work, Arnold Graffi received many honors and prizes, among them the Cothenius Medal (1977) from the Leopoldina in Halle, the Paul Ehrlich and Ludwig Darmstaedter Prize (1979) from the Paul Ehrlich Foundation in Frankfurt (shared with Otto Mühlbock and Wallace P. Rowe), and the Helmholtz Medal (1984) from the Academy of Sciences in Berlin. He was an honorary member of the European Association for Cancer Research (1981) and a corresponding member of the American Association for Cancer Research (since 1962). He was particularly proud to be awarded the Transsylvanian Cultural Prize (1979).

Throughout his life Graffi was seriously engaged in the arts. He was both a gifted painter (mainly watercolor landscapes, one was selected for the cover page of an October 1996 issue of the EMBO Journal) and a talented composer. He leaves a large collection of lovely pieces for piano. Remarkably, the organ music played at the funeral service for him included his own compositions.

In everything he did he was aided and encouraged by his wife, the biologist Dr. Inge Graffi. After retirement in 1976, he spent most of his time at home, which had always been a most important element in his later life. He was able to continue some research in the laboratory until the age of 78. Afterwards, he always remained in close contact with his many friends, discussing scientific and political issues with them. German reunification provided him with satisfaction, and he took a constant interest in the reshaping of his former Institute into the new Max Delbrück Center for Molecular Medicine. In 2003, he experienced that a new research building at the Campus Berlin-Buch was named after him.

Arnold Graffi leaves an extraordinary legacy of accomplishments in his long and productive career. He was a great scientist and a true humanist. He will be missed but not forgotten.