Towards a molecular characterisation of pathological pathways

The dominant conceptual reductionism in drug discovery has resulted in many promising drug candidates to fail during the last clinical phases, mainly due to a lack of knowledge about the patho-physiological pathways they are acting on. Consequently, to increase the revenues of the drug discovery process, we need to improve our understanding of the molecular mechanisms underlying complex cellular processes and consider each potential drug target in its full biological context. Here, we review several strategies that combine computational and experimental techniques, and suggest a systems pathology approach that will ultimately lead to a better comprehension of the molecular bases of disease.     

Giant sucking sound: can physiology fill the intellectual void left by the reductionists?

Molecular reductionism has so far failed to deliver the broad-based therapeutic insights that were initially hoped for. This form of reductionism is now being replaced by so-called "systems biology." This is a nebulously defined approach and/or discipline, with some versions of it relying excessively on hypothesis-neutral approaches and only minimally informed by key physiological concepts such as homeostasis and regulation. In this context, physiology is uniquely positioned to continue to provide impressive levels of both biological and therapeutic insight by using hypothesis-driven "classical" approaches and concepts to help frame what might be described as the "pieces of the puzzle" that emerge from molecular reductionism. The strength of physiology as a "bridge" between reductionism and epidemiology, along with its unparalleled ability to generate therapeutic insights and opportunities justifies increased attention and emphasis on our discipline into the future. Arguments relevant to this set of assertions are advanced and this paper, which was based on the 2011 Adolph Lecture, represents an effort to fill the intellectual void left by reductionism and improve scientific progress.     

Interspecies interactions within oral microbial communities.

While reductionism has greatly advanced microbiology in the past 400 years, assembly of smaller pieces just could not explain the whole! Modern microbiologists are learning "system thinking" and "holism." Such an approach is changing our understanding of microbial physiology and our ability to diagnose/treat microbial infections. This review uses oral microbial communities as a focal point to describe this new trend. With the common name "dental plaque," oral microbial communities are some of the most complex microbial floras in the human body, consisting of more than 700 different bacterial species. For a very long time, oral microbiologists endeavored to use reductionism to identify the key genes or key pathogens responsible for oral microbial pathogenesis. The limitations of reductionism forced scientists to begin adopting new strategies using emerging concepts such as interspecies interaction, microbial community, biofilms, polymicrobial disease, etc. These new research directions indicate that the whole is much more than the simple sum of its parts, since the interactions between different parts resulted in many new physiological functions which cannot be observed with individual components. This review describes some of these interesting interspecies-interaction scenarios.     

Fragments d’anthropologie clinique en action

The human condition means that both humaneness and inhumanity dwell in human beings, along with light and shadow, madness and reason. This ‘holistic’ conception of human life, which is based on the notion of drive, is under relentless threat from objectifying, psychiatric reductionism. Such impoverishment of the psyche is evident in neuroscience, sociologism and economism; the psyche is the locus of fragility, which constitutes the human condition and flows from the precarious balance between shadow and light in every person’s life. Psychiatry draws on the tendency of today’s society to eradicate evil, or at least make it invisible. This results in a world of hypertransparency, where negativity is obscured. Hence, life is deprived of destiny, of its tragic dimension, and of transcendence; it is under general anaesthesia, with no apparent suffering or pain. An anthropoclinical approach, which views human beings in their totality, offers an alternative to psychiatry’s objectification of the psyche. It goes beyond the alliance of the therapeutic and scientific and is driven by the ethical concern of a genuinely anthropological and clinical approach that allows meeting the Other in an existential union.     

Ins and Outs of Systems Biology vis-à-vis Molecular Biology: Continuation or Clear Cut?

The comprehension of living organisms in all their complexity poses a major challenge to the biological sciences. Recently, systems biology has been proposed as a new candidate in the development of such a comprehension. The main objective of this paper is to address what systems biology is and how it is practised. To this end, the basic tools of a systems biological approach are explored and illustrated. In addition, it is questioned whether systems biology ‘revolutionizes’ molecular biology and ‘transcends’ its assumed reductionism. The strength of this claim appears to depend on how molecular and systems biology are characterised and on how reductionism is interpreted. Doing credit to molecular biology and to methodological reductionism, it is argued that the distinction between molecular and systems biology is gradual rather than sharp. As such, the classical challenge in biology to manage, interpret and integrate biological data into functional wholes is further intensified by systems biology’s use of modelling and bioinformatics, and by its scale enlargement.     

On the decomposition of a dynamical system into non-interacting subsystems

It is shown that, under rather general conditions, it is possible to formally decompose the dynamics of ann-dimensional dynamical system into a number of non-interacting subsystems. It is shown that these decompositions are in general not simply related to the kinds of observational procedures in terms of which the original state variables of the system are defined. Some consequences of this construction for reductionism in biology are discussed.     

Bringing together emerging and endemic zoonoses surveillance: shared challenges and a common solution

Early detection of disease outbreaks in human and animal populations is crucial to the effective surveillance of emerging infectious diseases. However, there are marked geographical disparities in capacity for early detection of outbreaks, which limit the effectiveness of global surveillance strategies. Linking surveillance approaches for emerging and neglected endemic zoonoses, with a renewed focus on existing disease problems in developing countries, has the potential to overcome several limitations and to achieve additional health benefits. Poor reporting is a major constraint to the surveillance of both emerging and endemic zoonoses, and several important barriers to reporting can be identified: (i) a lack of tangible benefits when reports are made; (ii) a lack of capacity to enforce regulations; (iii) poor communication among communities, institutions and sectors; and (iv) complexities of the international regulatory environment. Redirecting surveillance efforts to focus on endemic zoonoses in developing countries offers a pragmatic approach that overcomes some of these barriers and provides support in regions where surveillance capacity is currently weakest. In addition, this approach addresses immediate health and development problems, and provides an equitable and sustainable mechanism for building the culture of surveillance and the core capacities that are needed for all zoonotic pathogens, including emerging disease threats.     

Increasing Consistency of Disease Biomarker Prediction Across Datasets

Microarray studies with human subjects often have limited sample sizes which hampers the ability to detect reliable biomarkers associated with disease and motivates the need to aggregate data across studies. However, human gene expression measurements may be influenced by many non-random factors such as genetics, sample preparations, and tissue heterogeneity. These factors can contribute to a lack of agreement among related studies, limiting the utility of their aggregation. We show that it is feasible to carry out an automatic correction of individual datasets to reduce the effect of such ‘latent variables’ (without prior knowledge of the variables) in such a way that datasets addressing the same condition show better agreement once each is corrected. We build our approach on the method of surrogate variable analysis but we demonstrate that the original algorithm is unsuitable for the analysis of human tissue samples that are mixtures of different cell types. We propose a modification to SVA that is crucial to obtaining the improvement in agreement that we observe. We develop our method on a compendium of multiple sclerosis data and verify it on an independent compendium of Parkinson''s disease datasets. In both cases, we show that our method is able to improve agreement across varying study designs, platforms, and tissues. This approach has the potential for wide applicability to any field where lack of inter-study agreement has been a concern.     

Emergentism as a default: Cancer as a problem of tissue organization

During the last fifty years the dominant stance in experimental biology has been reductionism. For the most part, research programs were based on the notion that genes were in ’the driver’s seat’ controlling the developmental program and determining normalcy and disease (genetic reductionism and genetic determinism). Philosophers were the first to realize that the belief that the Mendelian genes were reduced to DNA molecules was questionable. Soon after these pronouncements, experimental data confirmed their misgivings. The optimism of molecular biologists, fueled by early success in tackling relatively simple problems, has now been tempered by the difficulties found when attempting to understand complex biological problems. Here, we analyse experimental data that illustrate the shortcomings of this sort of reductionism. We also examine the prevailing paradigm in cancer research, the somatic mutation theory (SMT), the premises of which are: (i) cancer is derived from a single somatic cell that has accumulated multiple DNA mutations; (ii) the default state of cell proliferation in metazoa is quiescence; and (iii) cancer is a disease of cell proliferation caused by mutations in genes that control proliferation and the cell cycle. We challenge the notion that cancer is a cellular problem caused by mutated genes by assessing data gathered both from within the reductionist paradigm and from an alternative view that regards carcinogenesis as a developmental process gone awry. This alternative view, explored under the name of the tissue organization field theory (TOFT), is based on premises that place cancer in a different hierarchical level of complexity from that proposed by the SMT, namely: (i) carcinogenesis represents a problem of tissue organization comparable to organogenesis, and (ii) proliferation is the default state of all cells. We propose that the organicist view, in which the TOFT is based, is a good starting point from which to explore emergent phenomena. However, new theoretical concepts are needed in order to grapple with the apparent circular causality of complex biological phenomena in development and carcinogenesis.     

Cross-Study Projections of Genomic Biomarkers: An Evaluation in Cancer Genomics

Human disease studies using DNA microarrays in both clinical/observational and experimental/controlled studies are having increasing impact on our understanding of the complexity of human diseases. A fundamental concept is the use of gene expression as a “common currency” that links the results of in vitro controlled experiments to in vivo observational human studies. Many studies – in cancer and other diseases – have shown promise in using in vitro cell manipulations to improve understanding of in vivo biology, but experiments often simply fail to reflect the enormous phenotypic variation seen in human diseases. We address this with a framework and methods to dissect, enhance and extend the in vivo utility of in vitro derived gene expression signatures. From an experimentally defined gene expression signature we use statistical factor analysis to generate multiple quantitative factors in human cancer gene expression data. These factors retain their relationship to the original, one-dimensional in vitro signature but better describe the diversity of in vivo biology. In a breast cancer analysis, we show that factors can reflect fundamentally different biological processes linked to molecular and clinical features of human cancers, and that in combination they can improve prediction of clinical outcomes.     

Genetics in public health: Rarely explored

The availability and the integration of genetic information into our understanding of normal and abnormal growth and development are driving important changes in health care. These changes have fostered the hope that the availability of genetic information will promote a better understanding of disease etiology and permit early, even pre-symptomatic diagnosis and preventive intervention to avoid disease onset. Hence, our aim was to review and provide the insight into the role of genetics in public health and its scope as well as barriers. The use of genetics along with their goals and essential public health functions are discussed. From the era of eugenics to the present era, this area has seen many turns in which geneticists have put through their effort to tie together the strings of both molecular genetics and public health. Though still the dark clouds of eugenics, the predictive power of genes, genetic reductionism, non-modifiable risk factors, individuals or populations, resource allocation, commercial imperative, discrimination and understanding and education are hanging above. The technological and scientific advances that have fundamentally changed our perception of human diseases fuel the expectations for this proactive health.     

Rehabilitating Reductionism

SYNOPSIS: Reductionism has become the object of a great dealof criticism from a variety of quarters within evolutionarybiology in recent years. Many contemporary anti-reductionistsargue that reductionism is inappropriate in biological inquirygiven the prevalence of hierarchies, scales of complexity andlevels of organization in the organic world. They further contendthat a commitment to reductionism has led evolutionary theoriststo make a large number of methodological blunders and conceptualerrors in constructing explanations of biological evolution. The contemporary critics of reductionism have not made a persuasivecase for the ontological peculiarity of the organic world. Muchof their argument concerning hierarchy and levels appears torest on assertion rather than metaphysical necessity or ontologicalpeculiarity. Moreover, the interpretations of reductionism attackedby contemporary critics in biology are narrow and overly simplistic. The modern synthetic theory of evolution may well have explanatoryinadequacies that demand the attention of biologists workingin many fields. But attempts to motivate theoretical alternativesto this theory based solely on ontological grounds appear toplace the ontological cart before the theoretical horse. Theoriesdictate ontological commitments and, as a result, it is at thelevel of theoretical rather than ontological adequacy that theassessment of the modern synthetic theory ought to proceed.     

Biological complexity and drug discovery: a practical systems biology approach

Drugs fail in clinical studies most often from lack of efficacy or unexpected toxicities. These failures result from an inadequate understanding of drug action and follow, in part, from our dependence on drug discovery technologies that do not take into account the complexity of human disease biology. Biological systems exhibit many features of complex engineering systems, including modularity, redundancy, robustness, and emergent properties. Addressing these features has contributed to the successful design of an improved biological assay technology for inflammation drug discovery. This approach, termed Biologically Multiplexed Activity Profiling (BioMAP), involves the statistical analysis of protein datasets generated from novel complex primary human cell-based assay systems. Compound profiling in these systems has revealed that a surprisingly large number of biological mechanisms can be detected and distinguished. Features of these assays relevant to the behaviour of complex systems are described.     

Spontaneous tumours of pet dog as models for human cancers: searching for adequate guidelines.

Despite the ongoing search for "replacement" alternatives, animal models continue to play a crucial role in bio-medical research. However, both in vivo and in vitro models usually employed, such as rodents and/or cell lines, display intrinsic limits related to the specific characteristics of the biological systems used, whose management is very complex, and whose pathology, usually induced under artificial laboratory conditions, is frequently dissimilar to the studied human spontaneous disease. It has been suggested that carrying out clinical trials based on pre-clinical data obtained after a screening on animal models developing the neoplastic disease in a more similar way to human beings, as represented by spontaneous canine tumours, could accelerate the entry of new effective drugs into the clinical practice. In this paper the authors discuss the scientific foundation as well as the ethic and legal concerns related to the use of this "pet model" in comparative oncology, suggesting some "key words" as the necessary starting point for a correct approach to the matter.     

服务于人的生命科学和医学工作者必须坚持整体观*

在还原论、简化论的背景下,生理学和医学已经背离人体整体而从系统、器官、疾病等角度逐步细化,在带来医学科学进步的同时也显现出明显的缺陷和限制。从医学基础到临床各学科和分支学科之间亟需整合,人体健康管理、慢病预防、临床诊疗和功能康复等医学分支领域也亟需整合。人是不可分割的有机整体。作者以氧气需供代谢平衡为纲,以呼吸、血液循环、神经、代谢等系统联合一体化调控为基础,提出整体整合生理学医学新理论。唯物辩证地看待医学的专业细化和整合,以人为本,两者并重。医师应在继续强化专业化技术知识的同时,树立整体整合医学理念,以便为中国人民提供更优质和优化的防治医疗服务,并使之领先于世界。     

Vitamin E in the prevention of cardiovascular disease: the importance of proper patient selection

Vitamin E is a naturally occurring fat-soluble antioxidant which has been proposed as a treatment for both primary and secondary protection against cardiovascular (CV) events. Promising data from observational epidemiological studies associating higher vitamin E dietary intake with lower risk of CV events have not been validated in randomized controlled clinical trials assessing the effect of vitamin E on CV outcomes. While the pendulum of medical opinion has swung to suggest that high dose vitamin E supplements have no place in the treatment and prevention of CV disease, new data is emerging that allows identification of a specific target population for this treatment, namely patients with diabetes mellitus and the haptoglobin genotype 2-2. This review details the scientific basis and clinical evidence related to the effect of vitamin E on CV outcomes, and the importance of proper patient selection in gaining therapeutic benefit from this intervention.     

In defense of dignity: Reflections on the moral function of human dignity

This paper defends human dignity in two ways. First, by confronting the criticism that human dignity does not serve an important function in contemporary moral discourse and that its function can be sufficiently performed by other moral terms. It is argued that this criticism invites a danger of moral reductionism, which impoverishes moral discourse. The authority of moral philosophy to correct widely shared moral intuitions, rooted in experiences of grave injustices and wrongs, is questioned. Secondly, dignity is defended by showing what is needed to uphold it, both in theory and practice. It is argued, and demonstrated through examples, that human dignity as a universal value ascribed to human beings and the virtue of dignified action are intimately related. This is fleshed out in terms of Kant’s analysis of respect in the practical sense and of virtue as a commitment to the value of dignity as a constitutive end of our moral order. It is furthermore argued that theoretical attempts to ground respect for dignity in human capacities lead to a moral impasse. It is necessary to act as if every human being is worthy of respect. This practical approach requires institutions and specified moral obligations that are integral to the democratic ethos and the rule of law, which guarantees the equal status of human beings. This practical task requires that we consistently tease out and act on the implications of these principles rather than seek deeper justification for the equal worth of humans, articulated in the term human dignity.     

Pharmacogenetics in drug development

Over the last two decades, identification of polymorphisms that influence human diseases has begun to have an impact on the provision of medical care. The promise of genetics lies in its ability to provide insights into an individual's susceptibility to disease, the likely nature of the disease and the most appropriate therapy. For much of its history, pharmacogenetics (PGx-the use of genetic information to impact drug choice) has been limited to comparatively simple phenotypes such as plasma drug levels. Progress in genetics technologies has broadened the scope of PGx efficacy and safety studies that can be implemented, impacting on a broad spectrum of drug discovery and development activities. Recent PGx data show the ability of this approach to generate information that can be applied to dose selection, efficacy determination and safety issues. This in turn will lead to significant opportunities to affect both the approach to clinical development and the probability of success--the latter being an important aspect for pharmaceutical companies and for the patients who will benefit from these new medicines.     

Association of a Bacteriophage with Meningococcal Disease in Young Adults

Despite being the agent of life-threatening meningitis, Neisseria meningitidis is usually carried asymptomatically in the nasopharynx of humans and only occasionally causes disease. The genetic bases for virulence have not been entirely elucidated and the search for new virulence factors in this species is hampered by the lack of an animal model representative of the human disease. As an alternative strategy we employ a molecular epidemiological approach to establish a statistical association of a candidate virulence gene with disease in the human population. We examine the distribution of a previously-identified genetic element, a temperate bacteriophage, in 1288 meningococci isolated from cases of disease and asymptomatic carriage. The phage was over-represented in disease isolates from young adults indicating that it may contribute to invasive disease in this age group. Further statistical analysis indicated that between 20% and 45% of the pathogenic potential of the five most common disease-causing meningococcal groups was linked to the presence of the phage. In the absence of an animal model of human disease, this molecular epidemiological approach permitted the estimation of the influence of the candidate virulence factor. Such an approach is particularly valuable in the investigation of exclusively human diseases.