Alex Mauron

Constitutively expressed rat mRNA encoding a 70-kilodalton heat-shock-like protein.

A nearly full-length cDNA clone isolated from the rat pheochromocytoma cell line, PC12, revealed extensive nucleotide sequence similarity between the rat cDNA and the Drosophila melanogaster hsp70 gene. The rat recombinant clone encodes a 71,000-dalton protein that is 70% identical with the dipteran hsp70 protein. Remarkably, a truncated segment of this cDNA clone was originally isolated by immunoreactivity with antisera raised to catecholamine-synthesizing enzymes, suggesting that this heat shock protein and these catecholamine enzymes shared antigenic determinants. The rat hsp70-related mRNA is responsible for the production of a constitutive hsp70 protein, because it is present in abundant amounts in various tissues at normal growth temperatures and is only minimally induced by hyperthermia. The rat hsp70-related sequence is part of a multigene family that extends across species to mice and humans.

Autoimmune T lymphocytes in myasthenia gravis. Determination of target epitopes using T lines and recombinant products of the mouse nicotinic acetylcholine receptor gene.

Oligoclonal and cloned T lines from peripheral blood or thymuses of patients with myasthenia gravis (MG) were selected for reactivity against nicotinic acetylcholine receptors (AChR) from Torpedo california, or against a recombinant fusion peptide, X4, representing the extracellular portion of the mouse AChR alpha-chain. All cell lines expressed the CD4 membrane phenotype, and their antigen reactivity was blocked by antibodies against monomorphic HLA DR/DP determinants. Using a panel of fusion proteins of different, overlapping mouse AChR alpha-chain sequences, a major T cell epitope was localized between amino acid positions 85 and 142. This determinant was distinct from the humoral main immunogenic region, which has been identified on the sequence 61-76. The response pattern of uncloned T lines from three patients with different HLA haplotypes suggests, however, that in any one MG patient T lymphocytes may recognize more than one autoantigenic epitope on the AChR alpha-chain, and that the T lymphocyte response profiles vary among individual patients.

A question of method. The ethics of managing conflicts of interest

Conflicts of interest in biomedical research can endanger the independent judgement of researchers and, in a worst‐case scenario, can result in harm to humans, animals or the environment, or avoidable damage to scientifically validated truths. Highly publicized cases of scientists who have downplayed the risk of passive smoking—while receiving funding from the tobacco industry—or researchers who have questioned anthropogenic global climate change—yet are supported by the coal or oil industries—(LaDou et al , 2007) have attracted persistent, and often appropriate, criticism. A conflict of interest occurs when someone in a position of trust—for example, an academic researcher, lawyer or physician—has competing private and professional interests that make it more difficult to fulfil his or her professional duties without bias. However, a conflict of interest in itself is not necessarily bad, as long as the ‘right’ interests prevail. Nevertheless, conflicts of interest can create an impression of impropriety that, in the long run, might undermine the credibility of an individual or even an entire profession. At a time when policy‐makers, politicians and the public increasingly rely on scientific advice about controversial issues—for example, human embryonic stem cells, genetically modified crops or global climate change—conflicts of interest diminish the publics trust in the independence and unbiased judgement of academic scientists. To maintain trust, researchers must remain visibly trustworthy, which requires a careful and explicit management of conflicts of interest. Amidst growing concerns about the rising prevalence of conflicts of interest (Bekelman et al , 2003) and the attendant risks, various commentators and scientists have proposed several measures to handle conflicts of interest, which range from injunctions for more systematic disclosures to outright bans (Kaiser, 2005). > …a conflict of interest in itself is not necessarily bad, as long as the ‘right’ interests prevail Yet, research funding from private benefactors—who often pursue their own …

The ethics of palliative care and euthanasia: exploring common values

The ethical underpinnings of palliative care and those of voluntary euthanasia and assisted suicide (VE/AS) are often viewed as opposites. In this article, we review the values held in common by the euthanasia legalization movement and palliative care providers. Outlining this common ground serves to define, with greater clarity, the issues on which differences do exist, and ways in which some open questions, which are as yet unresolved, could be approached. Open discussion between VE/AS legalization advocates and palliative care providers is important to address these open questions seriously, and to enrich the care of terminally ill patients by giving members of both groups access to each other’s experience.

Pluripotent stem cells as new drugs? The example of Parkinson's disease

Cell replacement therapy is a widely discussed novel concept of medical treatment. The increased knowledge in the stem cell field, particularly pluripotent stem cells, potentially provides powerful tools for this therapeutic concept. A large number of disease characterized by the loss of functional cells are potential candidates for cell replacement therapy and, in this regards, Parkinsons disease is of particular interest. It is one of the most prevalent neurodegenerative diseases caused by the loss of dopaminergic neurons in the Substantia nigra pars compacta. Pharmacological therapies are valuable but suffer from the progressive decline of efficacy as the disease progresses. Cell therapy application has emerged about two decades ago as a valid therapeutic alternative and recent advances in stem cell research suggest that pluripotent stem cell transplantation may be a promising approach to replace degenerated neurons in Parkinsons disease. Various sources of pluripotent stem cells (PSC) currently tested in animal models of Parkinsons disease have proven their efficacy in relieving symptoms and restoring damaged brain function. This review summarizes and discusses the important challenges that actually must be solved before the first studies of PSC transplantation can be undertaken into humans.

Stem cell science: current ethical and policy issues

There is increasing support for embryonic stem (ES) cell research on both sides of the Atlantic. In the United States, the outcome is more funding from non‐federal sources, despite the current administrations opposing views. In Europe, a similar pragmatic turn is in the making, but the future is still uncertain. Acceptance of ES cells is mitigated by the uncritical belief that their use is ethically more suspect than is the case for adult cells.

Renovating the House of Being

Abstract: In recent years, the views of the German philosopher Peter Sloterdijk about humanism and the biological self‐engineering of mankind caused much turmoil in European intellectual circles. However, this is just one episode in a more general current controversy about the ethics of self‐manipulation, a debate that often centers around the recent progress in genomics and the possibility of shaping human genetic structure. The complete sequencing of the human genome has reinforced this focus. Making the human genome the object of a highly visible world‐wide research effort has reinforced popular notions stressing the centrality of the genome in defining individuality and humanity. As a result, proponents and opponents of the self‐engineering of human nature have often concentrated on technologies related to the genome. However, if one compares “genome‐based” and “brain‐based” explanations of Self and behavior, it turns out that neural aspects of human nature are more directly relevant. Many philosophical and ethical questions traditionally raised about genetics and genomics acquire more relevance and urgency when re‐examined in the context of neuroscience.

The choosy reaper

Our increased understanding of the biology of ageing has revived prospects for radical anti‐ageing medicine. Ethicists have often tried to argue against these endeavours, but with little success. Their arguments, which appeal to the natural order, are either circular or self‐defeating. Invoking the invariance of the human condition cuts no ice as rational argument and often turns into an avowedly irrational appeal to the ‘yuk reaction’ that exotic technologies evoke. Does that mean that anti‐mortality technologies are ethically innocuous? Not if we consider the reality of unequal death in todays world, in which differences in longevity highlight the gap between the haves and the have‐nots. Even in affluent societies, in which the basics of food, shelter and medicine are widely available, the grim reaper is very much class conscious. Without returning to the concern for equality that was once the hallmark of the Enlightenment, radical life extension may well add to these existing inequalities, and create more resentment and strife in the future. Many aspects of current biomedical research, especially in the more avant‐garde areas of neuroscience and stem‐cell research, are united under the alluring label ‘regenerative medicine’. These developments fuel legitimate hopes for new treatments of degenerative diseases, which, in an age of increasing longevity, represent the main focal point for prevailing anxieties about ill health and the frailties of old age. But regenerative medicine is often taken more literally to mean rejuvenation—a genuine turning back of the clock—which leads to more florid speculations about massive increases in human lifespan. These futuristic views are often criticized by scientists as daydreams that owe more to science fiction than to a sober appraisal of predictable advances. But they are taken more seriously by a different category of opponents, namely those who condemn these prospects on ethical grounds. For many conservative critics, …

Ethical Criteria for Human Trials of Stem-Cell-Derived Dopaminergic Neurons in Parkinson's Disease

A first-in-human, stem-cell-based trial for Parkinsons disease raises specific ethical issues. We analyze three challenges: participant selection, informed consent, and sham surgery. Phase I–II studies should recruit patients under 70 years of age with levodopa-responsive main features, free of nonmotor, levodopa-resistant symptoms and of complications of long-term dopamine replacement therapy. Recruitment should avoid the first months following diagnosis and exclude candidates for deep brain stimulation. A shorter overall life expectancy would be preferable to minimize cumulative risks of tumorigenesis. Participants should understand that research participation would not be a “last chance” scenario. Sham surgery would be unjustified as a placebo control in Phase I–II but may be required as a standardized negative, requiring intracranial injection, in Phase III trials. Potential participants fulfilling these conditions exist. Provided special precautions are taken with the design of first-in-human studies, such trials can be conducted in an ethically justified manner.

Experience of a multidisciplinary task force with exome sequencing for Mendelian disorders

BackgroundIn order to optimally integrate the use of high-throughput sequencing (HTS) as a tool in clinical diagnostics of likely monogenic disorders, we have created a multidisciplinary “Genome Clinic Task Force” at the University Hospitals of Geneva, which is composed of clinical and molecular geneticists, bioinformaticians, technicians, bioethicists, and a coordinator.Methods and resultsWe have implemented whole exome sequencing (WES) with subsequent targeted bioinformatics analysis of gene lists for specific disorders. Clinical cases of heterogeneous Mendelian disorders that could potentially benefit from HTS are presented and discussed during the sessions of the task force. Debate concerning the interpretation of identified variants and the content of the final report constitutes a major part of the task force’s work. Furthermore, issues related to bioethics, genetic counseling, quality control, and reimbursement are also addressed.ConclusionsThis multidisciplinary task force has enabled us to create a platform for regular exchanges between all involved experts in order to deal with the multiple complex issues related to HTS in clinical practice and to continuously improve the diagnostic use of HTS. In addition, this task force was instrumental to formally approve the reimbursement of HTS for molecular diagnosis of Mendelian disorders in Switzerland.