Reuniting philosophy and science to advance cancer research

Cancers rely on multiple, heterogeneous processes at different scales, pertaining to many biomedical fields. Therefore, understanding cancer is necessarily an interdisciplinary task that requires placing specialised experimental and clinical research into a broader conceptual, theoretical, and methodological framework. Without such a framework, oncology will collect piecemeal results, with scant dialogue between the different scientific communities studying cancer. We argue that one important way forward in service of a more successful dialogue is through greater integration of applied sciences (experimental and clinical) with conceptual and theoretical approaches, informed by philosophical methods. By way of illustration, we explore six central themes: (i) the role of mutations in cancer; (ii) the clonal evolution of cancer cells; (iii) the relationship between cancer and multicellularity; (iv) the tumour microenvironment; (v) the immune system; and (vi) stem cells. In each case, we examine open questions in the scientific literature through a philosophical methodology and show the benefit of such a synergy for the scientific and medical understanding of cancer.     

Immunohistochemical Localization of Neuropeptides and Neurotransmitters in the Nucleus Solitarius

The nucleus tractus solitarii (NTS), which receives visceralafferent information from the cardiovascular, respiratory, gastrointestinaland taste systems, contains multiple neurotrasmitters and neuropeptidesthroughout its rostral to caudal extent. The neurotransmittersand neuropeptides immunoreactivity is located predominatelyin varicose fibers and small puncta throughout the neuropil.In addition, immunoreactive NTS neurons for a variety of neurotransmittersand neuropeptides are present in subnuclear regions. The neuroactive substances localized immunohistochemically inthe NTS include acetylcholine, the neuropeptides, substanceP, methionine- and leucine-enkephalin, ß-endorphin,cholecystokinin, neurotensin, galanin, calcitonin gene-relatedpeptide, somatostatin, FMRMamide, neuropeptide Y, angiotensinII, vasoactive intestinal polypeptide, vasopressin, oxytocin,thyrotropin-releasing hormone, luteinizing hormone-releasinghormone, atrial natriuretic peptide, the catecholamines, dopamine,norepinephrine, epinephrine, serotonin, histamine and the aminoacids, GABA and glutamate. The pattern of innervation for eachneurotransmitter and neuropeptide is not homogeneously distributedthroughout the NTS. Each substance has a unique pattern withinthe NTS as each subnuclear region contains different immunohistochemicalstaining patterns and densities of fibers. At the ultrastructural level both neurotransmitters and neuropeptidesare present in synaptic terminals that are in contact with differentparts of the neuronal membranes. Typically, the labeled terminalscontain both small, clear vesicles and large, dense core vesicleswith the exception of synaptic terminals containing acetylcholine,GABA and glutamate which do not typically have the large, densecore vesicles. The most frequent post-synaptic target are dendritesand spinous processes. Less frequently, synaptic contacts arepresent on the cell soma. Chem. Senses 21: 367–376, 1996.     

Subunit structure of external invertase from Saccharomyces cerevisiae.

Because 50% of the mass of the external invertase of Saccharomyces cerevisiae consists of carbohydrate, it has been extremely difficult to obtain an accurate molecular weight of this enzyme by centrifugal or electrophoretic techniques. However, on removing almost all of the oligosaccharide chains of this enzyme with the endo-beta-N-acetyl-glucosaminidase H from Streptomyces plicatus, it has been possible to show that carbohydrate-free invertase is composed of two 60,000-dalton subunits. Terminal sequence analysis with carboxypeptidases A, B, and Y provided strong evidence that the subunits are identical.     

Potential inplications of endogenous aldehydes in beta-amyloid misfolding, oligomerization and fibrillogenesis

Aldehydes are capable of inducing protein cross-linkage. An increase in aldehydes has been found in Alzheimer's disease. Formaldehyde and methylglyoxal are produced via deamination of, respectively, methylamine and aminoacetone catalyzed by semicarbazide-sensitive amine oxidase (SSAO, EC 1.4.3.6. The enzyme is located on the outer surface of the vasculature, where amyloidosis is often initiated. A high SSAO level has been identified as a risk factor for vascular disorders. Serum SSAO activity has been found to be increased in Alzheimer's patients. Malondialdehyde and 4-hydroxynonenal are derived from lipid peroxidation under oxidative stress, which is also associated with Alzheimer's disease. Aldehydes may potentially play roles in beta-amyloid aggregation related to the pathology of Alzheimer's disease. In the present study, thioflavin-T fluorometry, dynamic light scattering, circular dichroism spectroscopy and atomic force microscopy were employed to reveal the effect of endogenous aldehydes on beta-amyloid at different stages, i.e. beta-sheet formation, oligomerization and fibrillogenesis. Formaldehyde, methylglyoxal and malondialdehyde and, to a lesser extent, 4-hydroxynonenal are not only capable of enhancing the rate of formation of beta-amyloid beta-sheets, oligomers and protofibrils but also of increasing the size of the aggregates. The possible relevance to Alzheimer's disease of the effects of these aldehydes on beta-amyloid deposition is discussed.     

Elephant Genomes Reveal Accelerated Evolution in Mechanisms Underlying Disease Defenses

Disease susceptibility and resistance are important factors for the conservation of endangered species, including elephants. We analyzed pathology data from 26 zoos and report that Asian elephants have increased neoplasia and malignancy prevalence compared with African bush elephants. This is consistent with observed higher susceptibility to tuberculosis and elephant endotheliotropic herpesvirus (EEHV) in Asian elephants. To investigate genetic mechanisms underlying disease resistance, including differential responses between species, among other elephant traits, we sequenced multiple elephant genomes. We report a draft assembly for an Asian elephant, and defined 862 and 1,017 conserved potential regulatory elements in Asian and African bush elephants, respectively. In the genomes of both elephant species, conserved elements were significantly enriched with genes differentially expressed between the species. In Asian elephants, these putative regulatory regions were involved in immunity pathways including tumor-necrosis factor, which plays an important role in EEHV response. Genomic sequences of African bush, forest, and Asian elephant genomes revealed extensive sequence conservation at TP53 retrogene loci across three species, which may be related to TP53 functionality in elephant cancer resistance. Positive selection scans revealed outlier genes related to additional elephant traits. Our study suggests that gene regulation plays an important role in the differential inflammatory response of Asian and African elephants, leading to increased infectious disease and cancer susceptibility in Asian elephants. These genomic discoveries can inform future functional and translational studies aimed at identifying effective treatment approaches for ill elephants, which may improve conservation.     

Properties of a defined mutant of Escherichia coli thymidylate synthase

A mutant of Escherichia coli thymidylate synthase (F3-TS), resulting from the replacement of a tyrosine for a cysteine 50 amino acids from the amino-terminal end, has been purified to homogeneity and found to contain less than 0.2% of the activity of the native enzyme (thyA-TS). Although this protein formed a ternary complex with 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP) and 5,10-methylenetetrahydrofolate, like the native enzyme, the extent of complex formation was significantly impaired as determined by equilibrium dialysis and circular dichroism. Thus, unlike the native enzyme, where 2 mol of FdUMP were present in each mole of ternary complex, F3-TS contained less than 1 mol of FdUMP/mol of ternary complex. Similarly, the binding of dUMP by F3-TS was greatly diminished relative to thyA-TS, but its binding as well as that of FdUMP could be improved by the presence of either the folate substrate or a tight binding folate analogue, 10-propargyl-5,8-dideazafolate (PDDF). However, despite the fact that PDDF enhanced the binding of FdUMP and dUMP to F3-TS, the binding of PDDF to the mutant enzyme was also greatly impaired. This contrasts with the native enzyme, which, under the same conditions, bound about 2 mol of PDDF/mol of enzyme in the presence or absence of either FdUMP or dUMP. Circular dichroism analyses with PDDF in the presence of dUMP or FdUMP yielded analogous results, but the effects were less dramatic than those obtained by equilibrium dialysis. Evidence in support of a structural difference between thyA-TS and F3-TS was obtained by demonstrating that the latter protein was 15-fold slower in forming a ternary complex with dUMP and PDDF than the former and that the mutant enzyme was less stable than the native enzyme.