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The Heidelberg Institute of Human Genetics celebrates its 50th anniversary

On the occasion of its 50th anniversary, the Institute of Human Genetics at the University Hospital of Heidelberg celebrates its major achievements in molecular genetic analyses, the diagnosis of hereditary diseases and tumour diseases as well as its research into the molecular causes of genetic defects. The largest institute of human genetics in Germany is also at the forefront of genetic counselling and debates on health policies and ethical issues.

When the chair of human genetics was established at the medical faculty of Heidelberg University in 1962, molecular genetics was still in its early phase of development. In 1961, Nirenberg and Matthaei had been the first to crack the first codon of the genetic code and Watson and Crick’s famous paper proposing that the DNA molecule has a double-helical structure had been published just nine years earlier in 1953. Considerable progress has since been made: the entire human genome, which consists of three billion nucleotides, can be sequenced in just a few days at a cost of only a few thousand euros and enormous progress is also being made in the identification of the genetic causes of diseases. 

The history of the Heidelberg Institute of Human Genetics reflects the enormous scientific progress that has been made in the fifty years since its inception. Through its important scientific results and technological developments, the institute has made considerable contributions to the development of human genetics in Germany and helped shape it into an interdisciplinary discipline that brings together basic research and clinical application. With over 100 employees, the Heidelberg Institute of Human Genetics is the largest of its kind in Germany, representing the entire range of human genetics research and application: the analysis of chromosomes and the study of developmental genes, cytodiagnostics and gene diagnostics as well as cancer research involving state-of-the-art laboratory methods and devices, including sequencing and SNP microarray analyses. The institute also offers genetic counselling and advice and is intensively involved with the ethical problems associated with technical and medical progress. 

First-ever drawing of human chromosomes, published in 1879 by Julius Arnold, professor of pathology in Heidelberg, in the journal “Archiv für Pathologische Anatomie”. © University Hospital Heidelberg

Discontinuity and new start

In Germany, modern human genetics is a relatively young field of science; it was only after 1960 that departments of genetics were established at German medical faculties on the recommendation of the Science Council. Of course, the roots of the discipline in areas such as chromosome research go back much further. Heidelberg is proud of the fact that the first-ever representation of human chromosomes was achieved by the Heidelberg pathologist Professor Dr. Julius Arnold in 1879.

But there was little continuity between these two dates, quite the opposite in fact: National Socialist racial fanaticism raged for many years with the “Law for the Prevention of Offspring with Hereditary Diseases”, the medical examination subject “Racial Hygiene” and the deadly euthanasia programme. Through excellent teaching and scientific activities and the establishment of research contacts and cooperations across the German border, Professor Dr. Friedrich Vogel, who founded and led what is now the Institute of Human Genetics for more than 30 years, did a great deal to restore the international reputation of German human genetics following the horrifying programmes in Nazi Germany.

Prof. Dr. Claus Bartram, Director of the Institute of Human Genetics and Dean of the Heidelberg Medical Faculty © University Hospital Heidelberg

In 1995, Professor Dr. Claus Bartram succeeded Professor Dr. Friedrich Vogel as chair of human genetics. He expanded the institute’s clinical areas and molecular genetics analyses with the aim of bringing it into line with state-of-the-art high-performance medicine. Friedrich Vogel also established the field of tumour genetics at the institute and transferred the institute’s genetic counselling services from the fields of research and diagnostics to a new Genetic Polyclinic. Bartram turned the institute into a German centre of human genetic diagnostics by offering special investigations involving molecular genetic and molecular cytogenetic methods, the analysis of hereditary tumour diseases and the identification of minute levels of cancer cells in tissue samples (known as “minimal residual disease”). Basic research at the institute was further strengthened with the establishment of the chair of molecular human genetics to which Professor Dr. Gudrun Rappold was appointed in 2003. 

Human genetics is becoming increasingly important

These days, molecular genetic investigations are part of many medical subjects; they are no longer a unique selling point of the field of human genetics. “However, the field of human genetics comes with a unique competence in the field of genetic counselling and the interpretation of genetic findings, which no other discipline is able to offer,” said Bartram in an interview given on the occasion of the 50th anniversary of his institute. He said that human genetics is indispensable for clinical applications and will in future play an even greater role than it does now. While the major focus was previously on monogenic diseases, which are relatively rare, human geneticists are now able to identify a person’s genetic disposition to disease for many common diseases and cancers. Based on the fact that whole genome sequencing is now technically and financially feasible, it can be safely assumed that these methods will be increasingly used for diagnostic and predictive medical applications. Which discipline, other than human genetics, is able to clinically discern relevant variants from the plethora of genetic variants and offer competent advice? More than 1,200 people come to the institute’s genetic polyclinic every year for advice. “We are here to answer any questions about potential genetic diseases,” said the director of the Genetic Polyclinic Dr. Dr. Ute Moog.

It goes without saying that the enormous technical possibilities also exacerbate the explosive nature of the ethical and legal problems associated with the increase in genetic knowledge. Ethical and legal issues were also dealt with intensively at a symposium held on 21st September 2012 at the German Cancer Research Center in Heidelberg on the occasion of the institute’s 50th anniversary. The symposium included talks given by Professor Dr. Jochen Taupitz, managing director of the Institute for German, European and International Medical Law and member of the German National Ethics Council, and Professor Dr. Klaus Tanner, theologian and ethicist at the University of Heidelberg. Bartram and Tanner are the instigators of the project “Ethical and legal aspects of the total sequencing of the human genome” (EURAT) at the University of Heidelberg’s Marsilius Kolleg (see BIOPRO article entitled "The EURAT project at the Marsilius Kolleg in Heidelberg").

Classical and molecular cytogenetics

Karyogram of a patient with chronic myeloid leukaemia (CML). The “Philadelphia translocation” (explanation in the text) is highlighted by arrows pointing at chromosome pairs 9 and 22. © University Hospital Heidelberg
Classical cytogenetics is still of huge importance for the diagnosis of genetic diseases. The Laboratory of Cytogenetics at the Heidelberg Institute of Human Genetics investigates samples from around 2,000 patients every year. Some genetic diseases can be identified efficiently by analysing the chromosomes of CML patients (karyogram) under a light microscope. One of these diseases is chronic myeloid leukaemia (CML), which is associated with the Philadelphia translocation, and is the first chromosomal abnormality in humans that has been linked to cancer. Philadelphia translocation relates to the translocation of segments between chromosomes 9 and 22 (see figure). During his research stay at the University of Rotterdam (NL), Bartram and his colleagues focused on the molecular characterisation of this genetic defect and found that the translocation results in the fusion of two genes.

Classical cytogenetics is complemented by fluorescence in situ hybridisation (FISH) which detects and localises the presence/absence of specific DNA sequences on chromosomes. The Heidelberg Institute of Human Genetics is a leader in the field of FISH analysis in Germany; it has access to a unique collection of genetic probes that are coupled with fluorescent dyes. These probes are mainly used in pre- and postnatal diagnoses and tumour diagnostics. MRD analysis, a method which was developed by Bartram and his team, is able to identify a single leukaemic cell in tens of thousands and even up to one million normal cells using PCR and specific probes. MRD is the acronym for “minimal residual disease” and refers to the small numbers of leukaemic cells that remain in the patient during or after treatment. MRD analysis is the method of choice for patients suffering from acute lymphatic leukaemia (ALL), which is the most frequent cancer in children. The identification of MRD cells enables suitable treatments aimed at preventing a recurrence of the tumour to be put in place. The continuous optimisation of diagnosis and therapy have contributed to the fact that currently more than 80 percent of all ALL patients can be treated successfully.

Developmental genes and growth factors

Professor Dr. Gudrun Rappold, Director of the Department of Molecular Human Genetics at the Institute of Human Genetics in Heidelberg. © University Hospital Heidelberg

In 1997, Gudrun Rappold and her team at the Institute of Human Genetics succeeded in identifying a gene whose mutated version leads to a specific type of short stature in children. The developmental gene SHOX (short stature homeobox containing gene) is located on the X chromosome and regulates the growth of the epiphyseal plate, and hence the longitudinal growth of bones. Clinical studies have shown that children with SHOX deficiency benefit from a treatment involving recombinant human growth hormone that enables them to gain around 15 cm in height. However, this treatment does not work when it comes to the majority of genetic growth disorders. The researchers from Heidelberg have also found that SHOX regulating genes on the X and Y chromosomes play an important role in other diseases, including a disease known as Léri-Weill dyschondrosteosis which is the result of mutations of distant enhancer sequences rather than mutations of the SHOX gene itself. 

Expression of the SHANK2 gene in a nerve cell © University Hospital Heidelberg

Another of Rappold and her team’s fields of research focuses on the molecular causes of mental disorders and autism. In 2010, the team isolated a gene called SHANK2 whose mutated form occurs in patients with autistic or mental disorders. SHANK2 codes for a scaffold protein found at the contact sites between nerve cells. Using a mouse model, the researchers have shown that the mutation of SHANK leads to morphological changes in the nerve cells (see: Defektes Gerüstprotein in Nervenzellen verursacht Autismus (Defective scaffolding protein associated with autism), in German only). Rappold and her team recently identified SHANK2 gene mutations in schizophrenia patients. “We are not yet able to say whether these mutations play a role in the pathogenesis of schizophrenia, it is possible that they exert their effect together with other genes. We need to carry out further research in order to find out more,” Gudrun Rappold said. Her group is part of the “German Mental Retardation Network” which is funded by the German Ministry of Education and Research (BMBF). The researchers carry out SNP microarray analyses with the aim of identifying new genes whose defective versions are associated with mental disorders. An SNP (single nucleotide polymorphism) is a DNA sequence variation that occurs when a single nucleotide differs between members of paired chromosomes in an individual. Working together alongside the Central Institute of Mental Health in Mannheim, the researchers have developed a mouse model in order to investigate the mechanisms underlying this gene defect. This cooperative project is funded under the “CellNetworks” cluster of excellence in Heidelberg.

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