Carlos M. Romeo-Casabona

Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia

Chronic lymphocytic leukaemia (CLL), the most frequent leukaemia in adults in Western countries, is a heterogeneous disease with variable clinical presentation and evolution. Two major molecular subtypes can be distinguished, characterized respectively by a high or low number of somatic hypermutations in the variable region of immunoglobulin genes. The molecular changes leading to the pathogenesis of the disease are still poorly understood. Here we performed whole-genome sequencing of four cases of CLL and identified 46 somatic mutations that potentially affect gene function. Further analysis of these mutations in 363 patients with CLL identified four genes that are recurrently mutated: notch 1 (NOTCH1), exportin 1 (XPO1), myeloid differentiation primary response gene 88 (MYD88) and kelch-like 6 (KLHL6). Mutations in MYD88 and KLHL6 are predominant in cases of CLL with mutated immunoglobulin genes, whereas NOTCH1 and XPO1 mutations are mainly detected in patients with unmutated immunoglobulins. The patterns of somatic mutation, supported by functional and clinical analyses, strongly indicate that the recurrent NOTCH1, MYD88 and XPO1 mutations are oncogenic changes that contribute to the clinical evolution of the disease. To our knowledge, this is the first comprehensive analysis of CLL combining whole-genome sequencing with clinical characteristics and clinical outcomes. It highlights the usefulness of this approach for the identification of clinically relevant mutations in cancer.

Non-coding recurrent mutations in chronic lymphocytic leukaemia.

Chronic lymphocytic leukaemia (CLL) is a frequent disease in which the genetic alterations determining the clinicobiological behaviour are not fully understood. Here we describe a comprehensive evaluation of the genomic landscape of 452 CLL cases and 54 patients with monoclonal B-lymphocytosis, a precursor disorder. We extend the number of CLL driver alterations, including changes in ZNF292, ZMYM3, ARID1A and PTPN11. We also identify novel recurrent mutations in non-coding regions, including the 3′ region of NOTCH1, which cause aberrant splicing events, increase NOTCH1 activity and result in a more aggressive disease. In addition, mutations in an enhancer located on chromosome 9p13 result in reduced expression of the B-cell-specific transcription factor PAX5. The accumulative number of driver alterations (0 to ≥4) discriminated between patients with differences in clinical behaviour. This study provides an integrated portrait of the CLL genomic landscape, identifies new recurrent driver mutations of the disease, and suggests clinical interventions that may improve the management of this neoplasia.

Embryonic Stem Cell Research and Therapy: The Need for a Common European Legal Framework

The possibility of obtaining stem cells from human embryos has given rise to an intensive legal and ethical debate. In this paper, attention is paid to the normative disparity and ambiguity in Europe. An argument for the need for a minimum legal harmonization is made; and a prudent and flexible way to reach this successfully is suggested. Establishing a common legal framework seems to be the only way to guarantee true competitiveness for the European scientific community.

Legal perspectives in novel psychiatric treatment and related research

The new generation of psychopharmacological products have proved their efficacy. Some neuro-degenerative diseases, such as Parkinson’s and Alzheimer’s diseases, could be treated by means of the gene therapy. Although the aetiology of such diseases is still not completely known, it has been proven that the patients lack some substances that could be produced by means of the transfer of in vivo or ex vivo genes that codify them in the proper places of the brain. Furthermore, it is announced that the implantation in laboratory grown stem cells of diverse origins is very hopeful. Cerebral (micro)electronic implants could be effective to fight some motor diseases as well as sensory functions. All of these kinds of new treatments need to be tested through clinical research. Most national legislation includes provisions on the clinical trials of drugs and a series of guarantees, procedures and conditions which are designed to ensure protection for individuals used in experiments and to assure that the trial is indeed of scientific relevance. However, few lay down similar regulations or provide for specific controls for the research of other treatments. Finally, enhancement of psychic capacities pose new problems for society as well as do the need for new legal decisions.ZusammenfassungEine neue Generation psychopharmakologischer Produkte hat ihre Wirksamkeit bewiesen. Manche neurodegenerative Krankheiten, zum Beispiel Parkinson und Alzheimer, konnten mit gentherapeutischen Methoden behandelt werden. Obgleich die Äthiologie solcher Krankheiten noch nicht ganz bekannt ist, konnte gezeigt werden, dass die betroffenen Patienten einen Mangel an bestimmten Substanzen aufweisen, der durch den Transfer von in vivo oder ex vivo Genen, in denen diese Substanzen kodiert sind, an die entsprechenden Stellen im Gehirn behoben werden kann. Außerdem setzt man inzwischen große Hoffnungen auf die Implantation der im Laboratorium kultivierten Stammzellen verschiedenen Ursprungs. Mit (mikro-)elektronischen Gehirnimplantaten könnten bald verschiedene motorische und sensorische Erkrankungen wirksam bekämpft werden. Bevor sie zur Anwendung kommen können, müssen all diese verschiedenen neuen Behandlungsmethoden einer klinischen Erprobung und klinischer Forschung unterzogen werden. In den meisten Ländern sind Gesetze in Kraft, die Bestimmungen hinsichtlich der klinischen Erprobung von Medikamenten enthalten und eine Reihe von Garantien, Prozeduren und Bedingungen vorsehen, die für die Sicherheit von Individuen sorgen sollen, die für solche Experimente herangezogen werden. Außerdem sollen diese Bestimmungen sicherstellen, dass die Versuche auch wissenschaftlich sinnvoll sind. Für die Erforschung anderer Behandlungsarten gibt es dagegen nur wenige gesetzliche Richtlinien, die eine ähnliche Regulation oder spezifische Kontrollmechanismen hinsichtlich der Erforschung dieser Behandlungsmethoden gewährleisten könnten. In diesem Zusammenhang stellen auch Maßnahmen zur Erhöhung psychischer Fähigkeiten die Gesellschaft vor neue Probleme und machen neue gesetzgeberische Entscheidungen notwendig.RésuméLa nouvelle génération de produits psychopharmaceutiques a fait la preuve de son efficacité. Certaines maladies neurodégénératives, comme les maladies de Parkinson et d’Alzheimer, ont pu être traitées au moyen de la thérapie génique. Bien que l’étiologie de telles maladies ne soit pas encore complètement connue, on a démontré qu’il manque aux patients certaines substances qui pourraient être produites par le transfert in vivo ou ex vivo de gènes qui les codifient au bon endroit dans le cerveau. En outre, on annonce comme très prometteuse l’implantation de cellules souches de diverses origines cultivées en laboratoire. Les implants cérébraux (micro-)électroniques pourraient s’avérer efficace pour lutter contre certaines affections motrices et des fonctions sensorielles. Tous ces types de nouveaux traitements doivent au préalable être testés par la recherche clinique. La plupart des législations nationales prévoient des clauses sur les essais cliniques de médicaments et mettent en place une série de garanties, de procédures et de conditions visant à assurer la protection des individus participant aux essais, et à veiller à ce que les essais ont effectivement une pertinence scientifique. Cependant, leurs réglementations sont rarement similaires et elles ne prévoient en général pas de contrôles spécifiques sur la recherche d’autres traitements. Enfin, l’amélioration des capacités psychiques pose de nouveaux problèmes pour la société, au même titre que le besoin en nouvelles décisions législatives.

Globalization and the Dynamic Role of Human Rights in Relation to a Common Perspective for Life Sciences

One is sure to note the growth and speed with which new discoveries and applications are being produced in the life sciences. This reflects the dynamism of the sector and the competitiveness that exists among different groups of researchers. One will also note the social perplexity that is being created by the novelties that are testing the foundations of long-established social perceptions and values. This perplexity also indicates that legal reasoning is often unable to offer efficient and/or calming answers. Cultural peculiarities, especially the moral, religious and legal traditions of different countries, states and nations entail relevant differences when dealing with the juridical framework of biomedicine. Nevertheless, when these assessments are carried over to human genetics, which in turn does not always connect solidly to previously well-defined axiological principles, it can often lead to quick changes in perception and even to the import of mimetic solutions by the policy makers. Paradoxically, these cultural divergences have been coexisting in some countries: their subjects accept ideological pluralism. In some cases, in order to re-examine concrete traditional assessments, especially those related to the respect and protection which human life in its different forms deserves, this pluralism has met strong resistance by ideological or religious groups. Resistance has also been met when confronted with new phenomena or realities, as for example in relation to the establishing of the critical moment of the beginning and of the end of human life (i.e. the ethical and legal status of the in-vitro human embryo as well as the decision to terminate a vital medical treatment). The finding of points of agreement on the acceptance or not of some life sciences’ novelties has been made more difficult due to such axiological divergences and ways of dealing with new situations.1 The researches which provide these novelties in the life sciences and specifically in human genetics and biotechnology frequently require neither additional

Is a Transcultural Law for Human Genetics and Biotechnology Possible

In this contribution the author suggests the necessity to find a new focus to the law related to genetics and biotechnology. Phenomena like globalization are not equal to the process of universalitation of values and goods to be protected by law. For a juridical approach to these matters it seems necessary to explore first the scientific and cultural contexts involved. Transculturality is an acceptable way to try to find common values that could be relevant to elaborate a universal legal framework for genetics and biotechnology. Then there is framework for harmonization, but giving anyway priority to universal recognized human rights. Human rights also present an objective dimension that permits through them the protection of realities or situations independent of the possibility of accepting the existence of a subject titleholder of a specific right. The challenge nowadays is to be able to recognize to human rights also a collective perspective. For Criminal Law specifically there is needed to avoid the recourse to a merely symbolic Law, in reference to which the legislator is more worried about expressing a moral and social rejection towards certain activities and to calm society than for an effective legal persecution of the same (as some are still in the future)

Law, Bioethics and Biosafety Regulations

The risks of uncontrolled dissemination of GMOs has made it clear that biosafety is a very relevant matter that goes beyond the State boundaries. This approach has had its corresponding reflection at the policy level, which reveals that the public powers and the legislators have been sensitive to this existing preoccupation in ever-growing sectors of society. From the European regulations, one can deduce a set of principles, which must guide the decisions of the public powers in matters related to biosafety: precaution, authorisation and inspection, “step by step”, “case by case”, traceability and transparency, among other.

The Place of Civil Law in Biotechnology

Biolaw is an autonomous interdisciplinary legal discipline, with great theoretical and practical relevance because of its possible social effects. This contribution deal with the most relevant different approaches to bioethical problems according to the main juridical systems, as they are civil law and common law. A main topic is also the relation between Biolaw, Bioethics and Biopolitics

Country Report Spain

1. Research in Medicine and in the Biological Sciences has gradually improved well-being and indeed the life expectancy of mankind. This is why nobody today disputes the importance of research in the field of the biomedical sciences, since progress in the latter depends largely on the results obtained through research. For this reason, biomedical research -leaving aside for the moment other considerations which I shall address further on- is viewed as first and foremost an asset of mankind in that it enables us to understand better the mechanisms of disease and illness, their causes and the means to prevent, combat or alleviate them. Research also helps fulfill one of the most burning desires of human nature: the quest for new knowledge. All this has received recognition in law. International and, more explicitly, national legal instruments recognise and protect freedom of scientific enquiry as a right, in many cases a fundamental one, and the authorities pledge themselves to the promotion of research.