It’s a great pleasure and privilege for me to present a short profile of our new Honorary member Professor Eric Engel, who proposed the concept of Uniparental Disomy (UPD) and pointed to its potential role in human genetic disease.

The premise
Eric Engel was educated at the Medical School of Geneva, Switzerland, in the field of Internal Medicine, and spent his post-doctoral years (1951-1960) in clinical training at the Geneva University Hospital. In this department, the main area of scientific interest was endocrinology, which subsequently led to the first identification of chromosomal disorders in abnormal gonadal developments, in the late 1950’s.

The turning point
In 1960, following a visit to Dr. Lejeune’s laboratory in Paris (Les Enfants Malades Hospital), he became a research fellow at US Massachusetts General Hospital (MGH) and Harvard Medical School in the Division of Endocrinology and the Thyroid Unit where he worked with A. P. Forbes and John Stanbury. At MGH, he set up a laboratory for the study of chromosomes, shifting the approach from fibroblasts to short term blood cultures. In the period 1960-1963, his main interest focussed on the sex chromosomal anomalies of endocrine patients, who provided him with the unique opportunity of studying most of the first described cases of Klinefelter and Turner syn-dromes. He pointed out the multiple underlying chromosomal abnormalities in these and allied conditions and their link with different clinical presentations.

The challenge
In 1963, one of the worlds leading endo-crinologists, G. W. Liddle, offered him the opportunity to start a Genetic Division at Vanderbilt University within the Department of Pediatrics. During the long and very active period at Vanderbilt (1963-1978) he promoted, with Walter E. Nance, the development of Genetics.
He addressed the study of chromosomal changes in both constitutional pathology (birth defects and congenital disorders) and haematological malignancies. With co-workers, he described chromosomal syndromes of partial deletion or duplication (such as the 11q- or 2p+ syndromes) and he demonstrated the duplication of Ph1 chromosome in blood cells of terminal CML, the occurrence of iso17q/iso18q in the acute phase of CML, a marker also of several lymphomas, as well as the first case of a hidden Ph1 chromosome (inserted into 17q).

He also described the apparent deletion of 17q in acute promyelocytic leukaemia, an anticipation of the t(15;17) translocation later identified by Janet Rowley in this subtype of acute myeloid leukaemia. He became acquainted with the segregation of somatic cell hybrids and the complementation studies of man-mouse heterokaryons, allowing the mapping of some human genes with Carlo Croce, of the Wistar Institute.

Despite all these basic research interests he always maintained his initial preference for clinical experience, nurtured from the constant practice of genetic counselling. As Director of the Genetics Center at Vanderbilt University Medical School, he worked on problems of infertility and recurrent abortions in the first trimester, and it was the high rate of chromosomal aberrations (trisomies and X-monosomies) in early pregnancy losses that stimulated his first reflections on the potential for complementation of gametes nullisomic and disomic for a same chromosome. This was the first conceptual frame work for thinking about Uniparental Disomy. Besides such a complemen-tation, trisomy and monosomy rescue through chromosome loss or duplication following maternal non-disjunction events were subse-quently put forward to account for UPD, in the two forms of heterodisomy and isodisomy.

The seminal breakthrough
In 1979 Eric Engel moved back to Geneva as chairman of the University Institute of Medical Genetics, within the Pediatrics Department, where he succeeded David Klein. He established a buzzing cytogenetics laboratory, where he further elaborated on the concept of uniparental disomy, with its attendant risk of recessive disorders, a risk later compounded by inter-ferences with genomic imprinting for some chromosomes and the residual effects from aneuploid/euploid mosaicism.

The concept was presented in a paper submitted to the American Journal of Medical Genetics. At that time its implications were speculative, as adequate molecular evidence was not yet available for parental chromosome polymorphisms to be identified. Credit must be given to the editor of the American Journal of Medical Genetics, John Opitz, for publishing in his Journal an advanced concept that awaited some 7 to 8 years for clinical confirmation. Indeed, at the American Society of Human Genetics Meeting in 1987, A. L. Beaudet presented a case with Cystic Fibrosis and maternal UPD7, published the year after in the AJHG (Spence et al., 1988). This case was followed by a number of other examples of UPD concerning different chromosomes and, by now a great body of evidence has been gathered on UPD and continues to unravel, pointing to the physiological role of genomic imprinting and setting some of the rules for the emerging area of non-Mendelian inheritance.

Coming back to the early eighties Eric Engel continued the interdisciplinary clinical-cytogenetic direction of the Medical Genetics Institute, introducing a DNA analysis laboratory in 1984.

He retired in 1991 and was succeeded by S. E. Antonarakis, of Johns Hopkins University. He continued to be involved in science, moving from Switzerland to France and the U.S. He has concentrated his activities on uniparental disomy and genomic imprinting, keeping into account all the new published evidence and critically reviewing the enormous body of data contributed all over the world. This ongoing updated knowledge was reflected in numerous reviews and lectures, and culminated in the release of a book with Stylanos Antonarakis on “Genomic Imprinting and Uniparental Disomy in Medicine”, published by Wiley-Liss, Inc. in 2001.

Address of the author:
Dipartimento di Biologia e Genetica per le Scienze Mediche
Via Viotti, 3/5
20133 MILANO
Tel.: +39 02 58 35 58 59
Fax : +39 02 58 35 58 64
e-mail: lidia.larizza@unimi.it