Covariance/Invariance: A Cognitive Heuristic in Einstein's Relativity Theory Formation

Relativity Theory by Albert Einstein has been so far littleconsidered by cognitive scientists, notwithstanding its undisputedscientific and philosophical moment. Unfortunately, we don't have adiary or notebook as cognitively useful as Faraday's. But physicshistorians and philosophers have done a great job that is relevant bothfor the study of the scientist's reasoning and the philosophy ofscience. I will try here to highlight the fertility of a `triangulation'using cognitive psychology, history of science and philosophy of sciencein starting answering a clearly very complex question:why did Einstein discover Relativity Theory? Here we arenot much concerned with the unending question of precisely whatEinstein discovered, that still remains unanswered, for we have noconsensus over the exact nature of the theory's foundations(Norton 1993). We are mainly interested in starting to answer the`how question', and especially the following sub-question: what(presumably) were his goals and strategies in hissearch? I will base my argument on fundamental publications ofEinstein, aiming at pointing out a theory-specific heuristic, settingboth a goal and a strategy: covariance/invariance.The result has significance in theory formation in science, especiallyin concept and model building. It also raises other questions that gobeyond the aim of this paper: why was he so confident in suchheuristic? Why didn't many other scientists use it? Where did he keep ? such a heuristic? Do we have any other examples ofsimilar heuristic search in other scientific problemsolving?     

The DNA sequence and biology of human chromosome 19

Chromosome 19 has the highest gene density of all human chromosomes, more than double the genome-wide average. The large clustered gene families, corresponding high G + C content, CpG islands and density of repetitive DNA indicate a chromosome rich in biological and evolutionary significance. Here we describe 55.8 million base pairs of highly accurate finished sequence representing 99.9% of the euchromatin portion of the chromosome. Manual curation of gene loci reveals 1,461 protein-coding genes and 321 pseudogenes. Among these are genes directly implicated in mendelian disorders, including familial hypercholesterolaemia and insulin-resistant diabetes. Nearly one-quarter of these genes belong to tandemly arranged families, encompassing more than 25% of the chromosome. Comparative analyses show a fascinating picture of conservation and divergence, revealing large blocks of gene orthology with rodents, scattered regions with more recent gene family expansions and deletions, and segments of coding and non-coding conservation with the distant fish species Takifugu.     

Electron-spin domains: magnetic enhancement of superconductivity

An inhomogeneous superconducting state, not yet conclusively identified, was predicted by Fulde and Ferrell and Larkin and Ovchinnikov (FFLO) to arise in superconductors with strong Pauli limiting, a consequence of the electrons' Zeeman (spin) energy in a magnetic field. Radovan et al. propose that the observed cascades of steps in magnetization of the heavy fermion superconductor CeCoIn5, within the recently discovered second low-temperature state, are due to transitions between Landau-level (LL) states with different m-quanta vortices, expected under certain conditions when the magnetic field is swept within the FFLO state. The authors then conclude that the observed steps in magnetization constitute a proof that the low-temperature state in CeCoIn5 is indeed an FFLO state. We argue that this interpretation of the observed steps in magnetization cannot be supported on either quantitative or qualitative grounds.     

Mutations in ENPP1 are associated with 'idiopathic' infantile arterial calcification

Idiopathic infantile arterial calcification (IIAC; OMIM 208000) is characterized by calcification of the internal elastic lamina of muscular arteries and stenosis due to myointimal proliferation. We analyzed affected individuals from 11 unrelated kindreds and found that IIAC was associated with mutations that inactivated ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1). This cell surface enzyme generates inorganic pyrophosphate (PP(i)), a solute that regulates cell differentiation and serves as an essential physiologic inhibitor of calcification.     

Identification of acquired somatic mutations in the gene encoding chromatin-remodeling factor ATRX in the alpha-thalassemia myelodysplasia syndrome (ATMDS)

Inherited mutations of specific genes have elucidated the normal roles of the proteins they encode by relating specific mutations to particular phenotypes. But many potentially informative mutations in such genes are lethal early in development. Consequently, inherited mutations may not reflect all the functional roles of such proteins. Acquired, somatic defects should reflect a wider spectrum of mutations because they are not prone to negative selection in development. It has been difficult to identify such mutations so far, but microarray analysis provides a new opportunity to do so. Using this approach, we have shown that in individuals with myelodysplasia associated with alpha-thalassemia (ATMDS), somatic mutations of the gene encoding the chromatin remodeling factor ATRX cause an unexpectedly severe hematological phenotype compared with the wide spectrum of inherited mutations affecting this gene. These findings cast new light on this pleiotropic cofactor, which appears to be an essential component rather than a mere facilitator of globin gene expression.     

Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome

We took advantage of overlapping interstitial deletions at chromosome 8p11-p12 in two individuals with contiguous gene syndromes and defined an interval of roughly 540 kb associated with a dominant form of Kallmann syndrome, KAL2. We establish here that loss-of-function mutations in FGFR1 underlie KAL2 whereas a gain-of-function mutation in FGFR1 has been shown to cause a form of craniosynostosis. Moreover, we suggest that the KAL1 gene product, the extracellular matrix protein anosmin-1, is involved in FGF signaling and propose that the gender difference in anosmin-1 dosage (because KAL1 partially escapes X inactivation) explains the higher prevalence of the disease in males.     

Mesenchymal stem cells within tumour stroma promote breast cancer metastasis

Mesenchymal stem cells have been recently described to localize to breast carcinomas, where they integrate into the tumour-associated stroma. However, the involvement of mesenchymal stem cells (or their derivatives) in tumour pathophysiology has not been addressed. Here, we demonstrate that bone-marrow-derived human mesenchymal stem cells, when mixed with otherwise weakly metastatic human breast carcinoma cells, cause the cancer cells to increase their metastatic potency greatly when this cell mixture is introduced into a subcutaneous site and allowed to form a tumour xenograft. The breast cancer cells stimulate de novo secretion of the chemokine CCL5 (also called RANTES) from mesenchymal stem cells, which then acts in a paracrine fashion on the cancer cells to enhance their motility, invasion and metastasis. This enhanced metastatic ability is reversible and is dependent on CCL5 signalling through the chemokine receptor CCR5. Collectively, these data demonstrate that the tumour microenvironment facilitates metastatic spread by eliciting reversible changes in the phenotype of cancer cells.