An assessment of the use of chimpanzees in hepatitis C research past, present and future: 1. Validity of the chimpanzee model

The USA is the only significant user of chimpanzees in biomedical research in the world, since many countries have banned or limited the practice due to substantial ethical, economic and scientific concerns. Advocates of chimpanzee use cite hepatitis C research as a major reason for its necessity and continuation, in spite of supporting evidence that is scant and often anecdotal. This paper examines the scientific and ethical issues surrounding chimpanzee hepatitis C research, and concludes that claims of the necessity of chimpanzees in historical and future hepatitis C research are exaggerated and unjustifiable, respectively. The chimpanzee model has several major scientific, ethical, economic and practical caveats. It has made a relatively negligible contribution to knowledge of, and tangible progress against, the hepatitis C virus compared to non-chimpanzee research, and must be considered scientifically redundant, given the array of alternative methods of inquiry now available. The continuation of chimpanzee use in hepatitis C research adversely affects scientific progress, as well as chimpanzees and humans in need of treatment. Unfounded claims of its necessity should not discourage changes in public policy regarding the use of chimpanzees in US laboratories.     

Physician assisted suicide: a new look at the arguments

In this paper, I examine the argumens agains physician assisted suicide (PAS). Many of these arguments are consequentialist. Consequentialist arguments rely on empirical claims about the future and thus their strength depends on how likely it is that the predictions will be realized. I discuss these predictions against the backdrop of Oregon's Death with Dignity Act and the practice of PAS in the Netherlands. I then turn to a specific consequentialist argument against PAS - Susan M. Wolfs feminist critique of the practice. Finally, I examine the two most prominent deontological arguments against PAS. Ultimately, I conclude that no anti-PAS argument has merit. Although I do not provide positive arguments for PAS, if none of the arguments against it are strong, we have no reason not to legalize it.     

Lessons from chimpanzee-based research on human disease: the implications of genetic differences

Assertions that the use of chimpanzees to investigate human diseases is valid scientifically are frequently based on a reported 98-99% genetic similarity between the species. Critical analyses of the relevance of chimpanzee studies to human biology, however, indicate that this genetic similarity does not result in sufficient physiological similarity for the chimpanzee to constitute a good model for research, and furthermore, that chimpanzee data do not translate well to progress in clinical practice for humans. Leading examples include the minimal citations of chimpanzee research that is relevant to human medicine, the highly different pathology of HIV/AIDS and hepatitis C virus infection in the two species, the lack of correlation in the efficacy of vaccines and treatments between chimpanzees and humans, and the fact that chimpanzees are not useful for research on human cancer. The major molecular differences underlying these inter-species phenotypic disparities have been revealed by comparative genomics and molecular biology - there are key differences in all aspects of gene expression and protein function, from chromosome and chromatin structure to post-translational modification. The collective effects of these differences are striking, extensive and widespread, and they show that the superficial similarity between human and chimpanzee genetic sequences is of little consequence for biomedical research. The extrapolation of biomedical data from the chimpanzee to the human is therefore highly unreliable, and the use of the chimpanzee must be considered of little value, particularly given the breadth and potential of alternative methods of enquiry that are currently available to science.     

The ubiquity of deception and the ethics of deceptive research

Does the fact that deception is widely practised – even though there is a general prohibition against deception – provide insight into the ethics of deceptive methods in research, especially for social‐behavioral research? I answer in the affirmative. The ubiquity of deception argument, as I will call it, points to the need for a concrete and nuanced understanding of the variety of deceptive practices, and thus promises an alternative route of analysis for why some deception may be permissible in social‐behavioral research. As an alternative argument it also promises to break the stalemate that emerges in debates on the ethics of deceptive methods in social‐behavioral research. In the current paper I (1) motivate and articulate the ubiquity argument in order to clarify the significance of ubiquity and discharge some initial objections. Then, on the recommendations of the ubiquity argument, I (2) highlight the importance of interpersonal relationships for understanding the ethics of deception. Following this insight I (3) provide an analysis of several features of the researcher‐participant relationship relevant to the understanding of the ethics of deception in research. I then (4) conclude the argument with some recommendations for the ethical use of deceptive methods in social‐behavioral research.     

Molecular and immunological significance of chimpanzee major histocompatibility complex haplotypes for hepatitis C virus immune response and vaccination studies

The chimpanzee is a critical animal model for studying cellular immune responses to infectious pathogens such as hepatitis B and C viruses, human immunodeficiency virus, and malaria. Several candidate vaccines and immunotherapies for these infections aim at the induction or enhancement of cellular immune responses against viral epitopes presented by common human major histocompatibility complex (MHC) alleles. To identify and characterize chimpanzee MHC class I molecules that are functionally related to human alleles, we sequenced 18 different Pan troglodytes (Patr) alleles of 14 chimpanzees, 2 of them previously unknown and 3 with only partially reported sequences. Comparative analysis of Patr binding pockets and binding assays with biotinylated peptides demonstrated a molecular homology between the binding grooves of individual Patr alleles and the common human alleles HLA-A1, -A2, -A3, and -B7. Using cytotoxic T cells isolated from the blood of hepatitis C virus (HCV)-infected chimpanzees, we then mapped the Patr restriction of these HCV peptides and demonstrated functional homology between the Patr-HLA orthologues in cytotoxicity and gamma interferon (IFN-gamma) release assays. Based on these results, 21 HCV epitopes were selected to characterize the chimpanzees' cellular immune response to HCV. In each case, IFN-gamma-producing T cells were detectable in the blood after but not prior to HCV infection and were specifically targeted against those HCV peptides predicted by Patr-HLA homology. This study demonstrates a close functional homology between individual Patr and HLA alleles and shows that HCV infection generates HCV peptides that are recognized by both chimpanzees and humans with Patr and HLA orthologues. These results are relevant for the design and evaluation of vaccines in chimpanzees that can now be selected according to the most frequent human MHC haplotypes.     

Treating lysosomal storage disorders: current practice and future prospects

There are over 40 human disease states that are caused by defects in various aspects of lysosomal function. Over the past two decades there has been dramatic progress in the development and evaluation of therapies for lysosomal storage disorders, several of which are now in routine clinical use or in clinical trials. The greatest current challenge is in developing effective therapies for treating the CNS manifestations of these complex disorders. In this article, we will review the current therapies/approaches being considered for treating lysosomal storage diseases and give a perspective on the scientific, medical, social and ethical issues they raise.     

Case study: Training a chimpanzee (Pan troglodytes) to use a nebulizer to aid the treatment of airsacculitis

Bacterial airsacculitis has been reported in a variety of nonhuman primates, and is widely treated using a combination of surgery and oral antibiotics. This case study details an alternative method of administering antibiotics (via the use of a nebulizer) when the chimpanzee subject developed resistance to all available oral preparations. Training the chimpanzee to use the nebulizer was performed using positive reinforcement techniques (PRT). It took a total of 89 sessions (<7 hr 25 min) to train the chimpanzee to use the nebulizer. The airsacculitis infection was treated using colistin in the nebulizer twice a day for 9 days. Out of 18 potential treatment sessions, full doses were administered on 13 occasions. The final dose of colistin was given via slow brachial intravenous injection under general anesthesia. The infection was successfully treated with colistin. Although there was a training time investment involved, it was felt to be outweighed by the success of the treatment. Also in the likelihood of the infection re-occurring at a later date, the now learnt behavior of using a nebulizer means that future treatment should now be considerably quicker. This is another example of how PRT is a useful tool in the successful welfare and management of captive animals.     

Chimpanzees in hepatitis C virus research: 1998–2007

Background  Chimpanzees have been widely used in hepatitis C virus (HCV) research, but their endangered status and high financial and ethical costs have prompted a closer review.
Methods  One hundred and nine articles published in 1998–2007 were analyzed for the number of chimpanzees involved, experimental procedures, objectives and other relevant issues.
Results  The articles described the use of 852 chimpanzees, but accounting for likely multiple uses, the number of individual chimpanzees involved here is estimated to be approximately 500. Most articles addressed immunology and inoculation studies. A significant portion of studies lasted for several months or years. Approximately one half of the individual chimpanzees were each used in 2–10 studies.
Conclusions  Significant financial and scientific resources have been expended in these chimpanzee HCV studies. Discussion addresses troublesome questions presented by some of the reviewed articles, including statistical validity, repeatability, and biological relevance of this model. These concerns merit attention as future approaches to HCV research and research priorities are considered.     

Reciprocal causation and the proximate–ultimate distinction

Laland and colleagues have sought to challenge the proximate–ultimate distinction claiming that it imposes a unidirectional model of causation, is limited in its capacity to account for complex biological phenomena, and hinders progress in biology. In this article the core of their argument is critically analyzed. It is claimed that contrary to their claims Laland et al. rely upon the proximate–ultimate distinction to make their points and that their alternative conception of reciprocal causation refers to phenomena that were already accounted for by standard theory.     

Role of antimicrobial peptides in host defense against mycobacterial infections

Worldwide, tuberculosis remains the most important infectious disease causing morbidity and death. Currently, at least one-third of the world's population is infected with Mycobacterium tuberculosis. In addition, the World Health Organization estimates that about 8-10 million new tuberculosis cases occur annually worldwide and this incidence is currently increasing. Moreover, multidrug-resistant tuberculosis has been increasing in incidence in many areas during the past decade. These situations underscore the importance of the development of new therapeutic agents against mycobacterial infectious diseases. In this article, it is review current progress in the understanding of antimicrobial peptides as potential candidates to develop an alternative/adjunct therapeutic strategy against tuberculosis. This immunoadjunctive therapy might be evaluated in the context of possible drug resistance. This review also summarizes the knowledge about the functions of antimicrobial peptides in the pulmonary innate host defense system and their role in mycobacterial infection, and at the same time outlines recent advances in our understanding of the combined effect of antimicrobial peptides and anti-tuberculosis drugs against intracellular mycobacteria. A concerted effort should now focus on the clinical application of antimicrobial peptides for their practical use.     

Analysis of the TCR beta variable gene repertoire in chimpanzees: identification of functional homologs to human pseudogenes

Chimpanzees are used for a variety of disease models such as hepatitis C virus (HCV) infection, where Ag-specific T cells are thought to be critical for resolution of infection. The variable segments of the TCR alphabeta genes are polymorphic and contain putative binding sites for MHC class I and II molecules. In this study, we performed a comprehensive analysis of genes that comprise the TCR beta variable gene (TCRBV) repertoire of the common chimpanzee Pan troglodytes. We identified 42 P. troglodytes TCRBV sequences representative of 25 known human TCRBV families. BV5, BV6, and BV7 are multigene TCRBV families in humans and homologs of most family members were found in the chimpanzee TCRBV repertoire. Some of the chimpanzee TCRBV sequences were identical with their human counterparts at the amino acid level. Notably four successfully rearranged TCRBV sequences in the chimpanzees corresponded to human pseudogenes. One of these TCR sequences was used by a cell line directed against a viral CTL epitope in an HCV-infected animal indicating the functionality of this V region in the context of immune defense against pathogens. These data indicate that some TCRBV genes maintained in the chimpanzee have been lost in humans within a brief evolutionary time frame despite remarkable conservation of the chimpanzee and human TCRBV repertoires. Our results predict that the diversity of TCR clonotypes responding to pathogens like HCV will be very similar in both species and will facilitate a molecular dissection of the immune response in chimpanzee models of human diseases.     

In vitro models for analysis of the hepatitis C virus life cycle

Chronic hepatitis C virus (HCV) infection affects approximately 170 million people worldwide. HCV infection is a major global health problem as it can be complicated with liver cirrhosis and hepatocellular carcinoma. So far, there is no vaccine available and the non-specific, interferon (IFN)-based treatments now in use have significant side-effects and are frequently ineffective, as only approximately 50% of treated patients with genotypes 1 and 4 demonstrate HCV clearance. The lack of suitable in vitro and in vivo models for the analysis of HCV infection has hampered elucidation of the HCV life cycle and the development of both protective and therapeutic strategies against HCV infection. The present review focuses on the progress made towards the establishment of such models.     

Biological and Health Science courses in New Zealand technical institutes

Argumentation in science is the process of coordinating theory and evidence to justify conclusions. This practice is at the heart of scientific journal writing and communication, but little is known regarding the argument quality of college science majors, the future scientists. Studies on written arguments at the college level have focused primarily on non-majors and upper-level students. To investigate and describe these skills throughout the biology curriculum, majors (n = 243) in four levels of undergraduate biology courses at a public university were assessed using a short, written argument instrument based on a hypothetical data set and scenario. Using Toulmin’s argumentation pattern to assess the instruments for argument aspects and quality, very few differences were found in the scores across course levels. Students were able to generate simple arguments consisting of claim, evidence and reasoning. The ability to provide scientific principles as reasoning to connect evidence and claims was positively correlated with course level. However, advanced argumentation skills, such as creating alternative explanations and rebuttals, were lacking across all course levels. These findings imply the need for explicit attention to argument construction throughout the undergraduate biology curriculum.     

ECVAM: desperately needed or superfluous? An animal welfare perspective

Eurogroup for Animal Welfare is the umbrella organisation of the major animal welfare organisations in Europe. Whereas its long-term goal is the complete replacement of animal experiments by methods that do not involve pain, suffering or distress in animals, it is also committed to any reasonable effort to reduce and refine animal experiments, as long as these continue to be carried out. Eurogroup therefore supports the activities of ECVAM, and it acknowledges the contributions to animal protection in various areas of animal use for scientific purposes made by ECVAM to date. Eurogroup is not satisfied with the number of alternative methods accepted in the past, but it sees the main responsibility for the slow progress as being outside ECVAM. The insufficient involvement of ECVAM by the EU Commission in various issues that would require its competence is also a matter of concern to Eurogroup.     

Autonomy,Natality and Freedom: A Liberal Re‐examination of Habermas in the Enhancement Debate

Jurgen Habermas has argued that carrying out pre‐natal germline enhancements would be inimical to the future child's autonomy. In this article, I suggest that many of the objections that have been made against Habermas' arguments by liberals in the enhancement debate misconstrue his claims. To explain why, I begin by explaining how Habermas' view of personal autonomy confers particular importance to the agent's embodiment and social environment. In view of this, I explain that it is possible to draw two arguments against germline enhancements from Habermas' thought. I call these arguments ‘the argument from negative freedom’ and ‘the argument from natality’. Although I argue that many of the common liberal objections to Habermas are not applicable when his arguments are properly understood, I go on to suggest ways in which supporters of enhancement might appropriately respond to Habermas' arguments.     

Non-human primate surrogate model of hepatitis C virus infection

More than 170 million people worldwide are chronically infected by HCV, which is the causative agent of chronic hepatitis C, cirrhosis, and finally liver cancer. Although animal models of viral hepatitis are a prerequisite for the evaluation of antiviral and vaccine efficacy, the restricted host range of HCV has hampered the development of a suitable small animal model of HCV infection. Use of the chimpanzee, the only animal known to be susceptible to HCV infection, is limited by ethical and financial restrictions. In this regard GBV-B, being closely related to HCV, appears to be a promising non-human surrogate model for the study of HCV infection. This review describes the characteristic of GBV-B infection of New World monkeys, and discusses current issues concerning the GBV-B model and its future directions.     

Are there morally acceptable alternatives to blastocyst derived ESC?

ESC derivation, use and SCNT have raised many moral and ethical issues. In this opinion piece I have focused on the argument that morally less ambiguous alternatives to ESC derived from the ICM of blastocysts exist. These possibilities range from using multiple adult stem cell populations each of which is uniquely suited for a particular disease target or identifying adult ESC-like populations, using transdifferentiated ESC-like cells or alternate methods of deriving ESC. I suggest that while it is important to support such efforts, current results do not provide sufficient compelling data to allow one to stop the use of ESC and perhaps adult cells will never be a reliable alternative. All options need to be fully explored and decisions need to be made with scientific rigor and respect for each individual's moral compass.     

Disciplinary baptisms: a comparison of the naming stories of genetics, molecular biology, genomics, and systems biology

Understanding how scientific activities use naming stories to achieve disciplinary status is important not only for insight into the past, but for evaluating current claims that new disciplines are emerging. In order to gain a historical understanding of how new disciplines develop in relation to these baptismal narratives, we compare two recently formed disciplines, systems biology and genomics, with two earlier related life sciences, genetics and molecular biology. These four disciplines span the twentieth century, a period in which the processes of disciplinary demarcation fundamentally changed from those characteristic of the nineteenth century. We outline how the establishment of each discipline relies upon an interplay of factors that include paradigmatic achievements, technological innovation, and social formations. Our focus, however, is the baptism stories that give the new discipline a founding narrative and articulate core problems, general approaches and constitutive methods. The highly plastic process of achieving disciplinary identity is further marked by the openness of disciplinary definition, tension between technological possibilities and the ways in which scientific issues are conceived and approached, synthesis of reductive and integrative strategies, and complex social interactions. The importance--albeit highly variable--of naming stories in these four cases indicates the scope for future studies that focus on failed disciplines or competing names. Further attention to disciplinary histories could, we suggest, give us richer insight into scientific development.     

Structure-based protein design with deep learning

Since the first revelation of proteins functioning as macromolecular machines through their three dimensional structures, researchers have been intrigued by the marvelous ways the biochemical processes are carried out by proteins. The aspiration to understand protein structures has fueled extensive efforts across different scientific disciplines. In recent years, it has been demonstrated that proteins with new functionality or shapes can be designed via structure-based modeling methods, and the design strategies have combined all available information — but largely piece-by-piece — from sequence derived statistics to the detailed atomic-level modeling of chemical interactions. Despite the significant progress, incorporating data-derived approaches through the use of deep learning methods can be a game changer. In this review, we summarize current progress, compare the arc of developing the deep learning approaches with the conventional methods, and describe the motivation and concepts behind current strategies that may lead to potential future opportunities.     

Current and Future Use of Nematodes in Biocontrol: Practice and Commercial Aspects with Regard to Regulatory Policy Issues

Constraints about the use of chemical insecticides have limited the availability of control measures against soil-borne insect pests. Entomopathogenic nematodes of the genera Steinernema and Heterorhabditis provide an environmentally safe and economically reasonable alternative. Their life cycle and current production, storage and formulation technology are described. An overview of their safety, use in integrated pest management and current market potential (US$10 million in 1994) is also given. The costs of research and development efforts and the scale-up of production technologies are discussed in relation to the current and future market potential. Large-scale, outdoor application will require additional scientific and technical progress in the areas of production, storage, formulation and application. Besides public funding, the current niche markets will need to provide the financial basis for further development, provided that regulatory conditions will not limit the exploitation of the nematodes' market potential. It is recommended that nematodes should be exempted from registration. Rules for risk assessment in the use of exotic nematodes should be internationally harmonized and related specifically to the biology and ecology of these nematodes. The volume of current markets would not justify the costs of registration procedures currently required for chemical or microbial insecticides or genetically engineered organisms. Regulatory policies should aim at supporting the further introduction of entomopathogenic nematodes as biocontrol agents.