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.     

Characterization of arginine as a solvent additive: a halophilic enzyme as a model protein

Arginine suppresses the aggregation of proteins. However, little is known about its mechanism. Here we have used HsNDK (Halobacterium salinarum nucleoside diphosphate kinase) to examine the solvent property of arginine. After exposure to 2 M arginine, HsNDK was diluted to a low salt buffer, resulting in fully active protein. Since unfolded HsNDK cannot refold in such low salt buffer, the observed activity indicates that HsNDK was in the native state in 2 M arginine. Enzyme activity was also examined directly in the presence of arginine, showing that it was active in the presence of 1 M arginine and, to less extent, 2 M arginine. Arginine, however, could not support refolding of heat-denatured HsNDK. HsNDK was stable at 40 degrees C for 19 h incubation in the presence of 1M arginine.     

N2O as a substrate and as a competitive inhibitor of nitrogenase

We have investigated the inhibitory effect of N2O on NH3 formation by purified component proteins from Klebsiella pneumoniae and have confirmed that the inhibition is competitive with respect to N2 and that N2O is reduced to N2, which in turn is further reduced to NH3. In addition, we have shown that N2O is unable to support HD formation from D2 and H2O. N2-supported HD formation from D2 and H2O was found to be inhibited by N2O. In contrast to N2, N2O was found to suppress nitrogenase-mediated H2 evolution completely at infinitely high pN2O. H2 was found to inhibit N2O-supported NH3 production but not N2O-supported N2 production. The steady-state kinetics of N2O reduction showed a good fit to Michaelis-Menten kinetics with a Km for N2O of 5 mM at 30 degrees C, corresponding to 24 kPa of N2O. A model is proposed that fits the observed results.     

An evaluation of carbon disulphide as a sulphur fertilizer and as a nitrification inhibitor

There was little release of extractable SO₄-S during four weeks from CS₂ applied by injecting into two S-deficient soils. In this incubation experiment, the rate of CS₂ was 30 μg S g⁻, placement was injection at 9 cm depth, soil temperature was 20°C, and soil moisture tension was 33 kPa. The yield of barley forage after seven weeks in the greenhouse showed only small increases from 10 or 30 μg S g⁻¹ of CS₂ as compared to Na₂SO₄, on the two soils. While CS₂ supplied little plant available S in the short term, it was an effective inhibitor of nitrification. In the laboratory, or in the field, the injection of CS₂ (with N fertilizers) at a point 9 cm into the soils either stopped or reduced nitrification. In one laboratory experiment, 35 μg of CS₂ g⁻¹ of soil with urea reduced nitrification for at least four weeks; and in another experiment 20 μg of CS₂ g⁻¹ of soil with aqua NH₃ nearly or completely inhibited nitrification at 20 days. In two field experiments, 3 and 12 μg of CS₂ g⁻¹ of soil (or 6 and 24 kg ha⁻¹) with aqua NH₃ inhibited nitrification from October to the subsequent May. In addition, CS₂ reduced the amount of ammonium produced from the soil N, both in these two field experiments and in the laboratory experiments. That is to say, CS₂ injected at a point, inhibited both nitrification and ammonification. In other field experiments, CS₂ at a rate of 10 kg ha⁻¹ was injected in bands 9 cm deep with urea in October, and by May there was still reduced nitrification. Less than half of the fall-applied urea alone was recovered as mineral N, but with the application of CS₂ the recovery was increased to three-quarters. The yield and N uptake of barley grain was increased where fall-applied banded urea or aqua NH₃ received banded CS₂, (NH₄)₂CS₃, or K₂CS₃. The average increase in yield from fall-applied fertilizer, from inhibitor with fall-applied fertilizer, and from spring-applied fertilizer was 800, 1370, and 1900 kg ha⁻¹, respectively. In the same order, the apparent % recovery of fertilizer N in grain was 24, 42, and 60.     

A review of curcumin as a biological stain and as a self-visualizing pharmaceutical agent

Curcumin has been widely used to color textiles but, unlike other natural dyes such as hematoxylin or saffron, it rarely has been discussed as a biological stain. Aspects of the physicochemistry of curcumin relevant to biological staining and self-visualization, i.e., its acidic properties, lipophilicity, metal and pseudometal complexes, and optical properties, are summarized briefly here. Reports of staining of non-living biological specimens in sections and smears, both fixed and unfixed, including specimens embedded in resin, are summarized here. Staining of amyloid, boron and chromatin are outlined and possible reaction mechanisms discussed. Use of curcumin as a vital stain also is described, both in cultured monolayers and in whole organisms. Staining mechanisms are considered especially for the selective uptake of curcumin into cancer cells. Staining with curcumin labeled nanoparticles is discussed. Toxicity and safety issues associated with the dye also are presented.     

Gulose as a constituent of a glycoprotein.

The aldohexose gulose was identified as a constituent of a hydroxyproline-rich glycopeptide derived from the glycoprotein SSG 185. This glycoprotein is part of the extracellular matrix of the green alga Volvox carteri. The gulose residue occupies a terminal position in the corresponding saccharide.