Why is melanoma so metastatic?

Malignant melanoma is one of the most aggressive cancers and can disseminate from a relatively small primary tumor and metastasize to multiple sites, including the lung, liver, brain, bone, and lymph nodes. Elucidating the molecular and genetic changes that take place during the metastatic process has led to a better understanding of why melanoma is so metastatic. Herein, we describe the unique features that distinguish melanoma from other solid tumors and contribute to the malignant phenotype of melanoma cells. For example, although melanoma cells are highly antigenic, they are extremely efficient at evading host immune response. Melanoma cells share numerous cell surface molecules with vascular cells, are highly angiogenic, are mesenchymal in nature, and possess a higher degree of ‘stemness’ than do other solid tumors. Finally, analysis of melanoma mutations has revealed that the gene expression profile of malignant melanoma is different from that of other cancers. Elucidating these molecular and genetic processes in highly metastatic melanoma can lead to the development of improved treatment and individualized therapy options.     

Why is mimicry in cuckoo eggs sometimes so poor?

I propose that the existence of imperfect adaptations (e.g. egg mimicry) in brood parasites and their hosts (e.g. discrimination abilities) could reflect age-dependent territory and nest-site selection patterns of the host. Studies of various passerines indicate that (1) older breeders tend to occupy nest sites of higher quality than do young birds (ideal despotic distribution resulting from interference competition), (2) nest-site selection affects the risk of parasitism in various habitats, (3) egg recognition in passerines has a strong learning component (therefore naive breeders tend to accept whereas older birds tend to reject parasitic eggs). Because young naive birds, who tend to accept parasitic eggs, usually breed in low-quality areas where they are frequently parasitised, while old experienced birds, who tend to reject parasitic eggs, breed in high-quality areas where they are rarely parasitised, the distribution of acceptors and rejecters with respect to the risk of parasitism is non-random, i.e. populations of some host species may consist of heavily parasitised acceptors and weakly parasitised rejecters. Therefore, the selection pressure exerted by the host on the parasite should be weaker than if brood parasitism was randomly distributed among naive and experienced breeders and affect adaptations such as egg mimicry. This could explain the existence of imperfect adaptations in some brood parasite-host systems.     

Why is there so little intragenic linkage disequilibrium in humans?

The efficient design of association mapping studies relies on a knowledge of the rate of decay of linkage disequilibrium with distance. This rate depends on the population recombination rate, C. An estimate of C for humans is usually obtained from a comparison of physical and genetic maps, assuming an effective population size of approximately 10(4). We demonstrate that under both a constant population size model and a model of long-term exponential growth, there is evidence for more recombination in polymorphism data than is expected from this estimate. An important contribution of gene conversion to meiotic recombination helps to explain our observation, but does not appear to be sufficient. The occurrence of multiple hits at CpG sites and the presence of population structure are not explanations.     

Why is dracunculiasis eradication taking so long?

The long time needed for global eradication of dracunculiasis (Guinea worm disease) was not anticipated at the outset. The successful eradication of smallpox in 10 years compares with the target date set in 1985 for dracunculiasis eradication - 1995. Seventeen years after that date, transmission continues. Why? Various factors are responsible, mainly lack of resources, or resources ineffectively used. The example of Ghana, where the programme stagnated for a decade, sheds light on this delay. When more resources were put into Ghana's programme in 2007, transmission of the disease was interrupted in 3 years. The variable success of dracunculiasis eradication in different countries provides lessons for future disease eradication programmes.     

Why is an energy metabolic defect the common outcome in BMFS?

Inherited bone marrow failure syndromes (BMFS) are rare, distressing, inherited blood disorders of children. Although the genetic origin of these pathologies involves genes with different functions, all are associated with progressive haematopoietic impairment and an excessive risk of malignancies. Defects in energy metabolism induce oxidative stress, impaired energy production and an unbalanced ratio between ATP and AMP. This assumes an important role in self-renewal and differentiation in haematopoietic stem cells (HSC) and can play an important role in bone marrow failure. Defects in energetic/respiratory metabolism, in particular in FA and SDS cells, have been described recently and seem to be a pertinent argument in the discussion of the haematopoietic defect in BMFS, as an alternative to the hypotheses already established on this subject, which may shed new light on the evolution of these diseases.     

Why is revitalizing clinical research so important, yet so difficult?

We believe that support for academic clinical research has greatly declined in recent decades. Here we discuss our views on why this has happened. We define clinical or patient-oriented research as limited to the study of human beings or populations of individuals, and argue that its eclipse in favor of basic and "translational" research is the result of inappropriate conceptual paradigms or "models" for medical advances. We believe that medical history shows that the "bench-to-bedside" model is inadequate to explain most recent progress and that clinical advances themselves often lead to new basic research. Discussion of alternate conceptual frameworks for biomedical research should help lead to changes in funding and organizational structures that might finally revitalize clinical research.     

Why is the house mouse karyotype so variable?

rates of robertsonian chromosomal evolution in the Western European house mouse are about two orders of magnitude greater than for most other mammals. This has resulted in a remarkable diversity of karyotypic races in a very short period of time. Recent studies are beginning to shed light on the relative contributions of mutation, drift, selection and meiotic drive in producing this pattern.     

Why is stress so deadly? An evolutionary perspective

The reaction of the body to prolonged stress has many harmful effects. Classical theory assumes that stress responses have evolved due to their short-term selective advantages ('flight or fight'), and despite their adverse long-term effects. In contrast, we demonstrate that the adverse effects of stress responses may have a selective advantage. Using an analytical model we show that a gene that causes the early death of a relatively unfit individual can increase in frequency in a structured population even if it has no positive effect on that individual. This result offers a new perspective on the relations between stress factors, stress responses and stress-related diseases.     

Why is the cystic fibrosis gene so frequent?

Summary The high incidence of cystic fibrosis (CF) in most European populations (and populations of European descent) can be explained by different hypotheses that can be tested using the available data concerning this disorder. Among the five hypotheses discussed (genetic heterogeneity, high rate of mutation, meiotic drive, drift and heterozygote advantage), only the last is supported by experimental data. The following conclusions can be drawn from the evidence that we have reviewed: (1) CF is a single gene disorder (genetically homogeneous). (2) Haplotypes associated with the CF gene suggest that only a few mutations (the same gene located in 7q13 is always affected) are responsible for the disorder. (3) CF with pancreatic insufficiency is mainly associated with a single haplotype, whereas CF with pancreatic sufficiency is more frequently associated with different haplotypes. (4) A selective advantage consisting of higher resistance to Cl^–-secreting diarrhoeas might have favored, in the past, survival of infants heterozygous for the CF gene.     

Why so few?

Nobel Prize Women in Science: Their struggles and momentous discoveries (1998). S. Bertsch McGrayne. Carol Publishing Group, 448 pp. $19.95 paper ISBN 0806520256.     

Why is Deinococcus radiodurans so resistant to ionizing radiation?

When exponential-phase cultures of Deinococcus radiodurans are exposed to a 5000-Gray dose of gamma radiation, individual cells suffer massive DNA damage. Despite this insult to their genetic integrity, these cells survive without loss of viability or evidence of mutation, repairing the damage by as-yet-poorly-understood mechanisms.