The huge technological progress that will in the near future make the total sequencing of individual human genomes a customary procedure that can be carried out relatively quickly and at reasonable cost, opens up new prospects for “individualised medicine” that can adapt the diagnosis, therapy and prevention of disease more accurately to a patients’ genetic variability.

But these new technical capabilities have also triggered controversy relating to the ethical and legal implications for which society is insufficiently prepared. Scientists from the University and University Hospital of Heidelberg, the German Cancer Research Center (DKFZ), the European Molecular Biology Laboratory (EMBL) and the Max Planck Institute for Comparative Public Law and International Law, have joined forces in an interdisciplinary project on the ethical and legal aspects, in order to achieve a concerted viewpoint and come up with proposals for solutions.

The interdisciplinary project “Ethical and legal aspects of the total sequencing of the human genome”, which involves bioinformaticians, human geneticists, molecular biologists, oncologists, pathologists, lawyers and theologians, is being carried out at Heidelberg University’s Marsilium Kolleg. It was officially started with a lecture by Professor Claus Bartram, human geneticist and Dean of the Heidelberg Medical Faculty, held in the “Alte Aula” auditorium on 19th May 2011 as part of the celebration of Heidelberg University’s 625th anniversary. Bartram’s talk was entitled “The total sequencing of the human genome: biomedical and socio-political importance of a technical revolution”. Prior to the official go-ahead, the spokespeople for the project, Professor Klaus Tanner from the Scientific and Theological Seminary of the University of Heidelberg, and the molecular biologist and cancer researcher Professor Peter Lichter from the DKFZ, discussed the cultural and technical framework as well as the ethical and legal aspects of the total sequencing of the human genome.

In addition to Bartram, Lichter and Tanner, the EURAT project group also involves seven other outstanding scientists from Heidelberg with comprehensive knowledge about genome sequencing, molecular biology, bioinformatics, oncology, pathology, biobanking, constitutional and comparative law. The project is managed and coordinated at the Marsilius Kolleg by Dr. phil. Grit Schwarzkopf.

Around ten years ago, when the total sequencing of a human genome was being heavily publicized by politicians and the media, many people believed that this would mark the onset of a new era of individual medicine: “We are on the leading edge of a true revolution in medicine, one that promises to transform the traditional ‘one size fits all’ approach into a much more powerful strategy that considers each individual as unique and as having special characteristics that should guide an approach to staying healthy.” This prophecy comes from the geneticist Francis Collins (present director of the National Institutes of Health, USA), who, as head of the Human Genome Project, was one of the protagonists in the deciphering of the human genome (F. S. Collins: The Language of Life: DNA and the Revolution in Personalized Medicine, 2011).

As Klaus Tanner pointed out in his talk given at the Marsilius Kolleg on 2nd May 2011, the German Federal Ministry of Education and Research expected human genome research to establish the genetic makeup of a human as the starting point for the detection and treatment of causes of disease and that the Human Genome Project would lead to the identification of the genetic alterations that cause the 10,000 or so known diseases.

In the intervening period, even some early enthusiasts have become somewhat disillusioned. Nobel Laureate Harold Varmus wrote (N Engl J Med 362, p. 2028; 2010): "Now, after the first decade of a postgenome world, only a handful of major changes - some gene-specific treatments for a few cancers, some novel therapies for a few mendelian traits, and some strong genetic markers for assessing drug responsiveness, risk of disease, or risk of disease progression - have entered routine medical practice." The majority of this progress results from discoveries that preceded the deciphering of the human genome. Varmus concludes that genomics and related disciplines are still more closely related to modern sciences than to modern medicine. He added that the disciplines created broad knowledge but that this new information has only been used in a few cases as the rule for risks, disciplines and therapies.

No-one questions the fact that huge technical progress has been made in genomics and related disciplines. This dynamic creates new challenges not only in the field of medicine but in society as a whole. The draft version of the human genome assembled from the DNA sequences of many individuals from all continents took around seven years to complete and cost three billion US dollars, the sequencing of the first complete individuals (i.e. the discoverer of DNA, James Watson, and his rival, the biotechnology pioneer Craig Venter) in 2007 cost around one million dollars. In his opening lecture, Claus Bartram stated that the genomes of around 1,000 people have since been sequenced for a price of just 20,000 dollars per sequence. He expressed his belief that it will soon be possible to sequence entire human genomes in just a few days for as little as 1,000 dollars. “Costing just 1,000 dollars and taking only a few days to complete, I believe that sequencing will soon enter the realms of medicine; however, we are ill prepared to deal with the implications of this development for medicine and society as a whole,” said Bartram. “We need to discuss the changes that will be brought about by this technology and the risks it involves, however controversial this is.”

The sequencing of the human genome revealed a surprisingly high interindividual variability of the human genome: every human has around 15 million SNPs (“single nucleotide polymorphisms”), which means that the human genome differs in around one in 200 DNA base pairs. In addition, the sequencing efforts revealed that entire genes and long stretches of DNA are present in different copy numbers, which might lead to genetic diseases or disposition to disease. The strongest advocators of genome-based medicine are cancer researchers who are faced with the fact that almost all tumour and cancer patients differ from one another. Gliomas, breast and bowel cancer frequently contain 10,000 or more somatic mutations, lung cancer and melanomas contain even more. The objective of the International Cancer Genome Consortium (ICGC) is to analyse 25,000 genomes of 50 different cancer types and their respective healthy tissues.

The ICGC also focuses on the investigation of gene expression regulation, the transcriptome and epigenetic modifications. In the ICGC, Peter Lichter from the DKFZ coordinates the analysis of paediatric brain tumours, which are the major cause of cancer-related deaths in young children. Genome analyses improve our knowledge of the development of diseases, diagnoses, therapies and prevention, thereby creating the basis for a personalized medicine that enables an efficient application of drugs.

According to Leroy Hood, a pioneer of systems biology and sequencing technology, there are already hundreds of known genetic variants that have an influence on the diseases we contract, and that affect our ability to tolerate drugs and dictate the quantity we need to take.

Any diagnostic procedure requires the “informed consent” of a patient or volunteer, which refers to the consent given once a person clearly appreciates and understands the information provided as well as the potential outcome and its significance. But what does “informed consent” mean in terms of the total sequencing of the human genome? At present, it is assumed that any human possesses around 100 or more disease-relevant factors, some of which have a high power of prognosis, others only a little. Even if data analysis is restricted to certain problem fields, for example cancer, there is still the question as to how surplus information should be dealt with. Numerous disease genes do not lead to disease when present in heterozygous form, this only occurs when both genes are affected. Does this mean that a couple should undergo heterozygote screening when they plan to have children together?

How should a person’s right not to know be dealt with, especially in cases such as Huntington’s disease, which can be predicted but for which no therapy is available? Bartram described the conflict that arises when, for example, a paternal grandmother has Huntington’s disease and her grandchild wants to have his or her genotype tested, but her son, the grandchild’s father, does not. Predictive diagnostics not only have to take into account the right of not wanting to know of the person seeking advice, but also the right of this person’s relatives. Issues to be addressed also include the accuracy and significance of other medically relevant data, in particular individual patient data and information stored in tissue banks. How can privacy and confidentiality be protected? How realistic is it to believe that a person is protected by the “anonymisation” of data even though short DNA sequences enable individuals to be clearly identified? How is it possible to prevent genome research from leading to genetic discrimination by employers or insurance companies?

In the bioethical guidelines and rules that the University Hospital, EMBL, DKFZ and the tissue bank of the National Centre for Tumour Diseases follow, problem areas associated with the total sequencing of human genomes are only dealt with rudimentarily. Even the Gene Diagnostics Law, which became effective in February 2010, falls short of addressing how the application of new technical possibilities can be effectively regulated. Claus Bartram believes that the Law creates more problems than solves. The EURAT project is designed to deal with the aforementioned as well as other ethical and legal consequences of total genome sequencing, come up with a concerted viewpoint and provide advice.