Biomedical subjects

Robert Root-Bernstein

Publications and source records attributed to Robert Root-Bernstein.

7 recordsLinked to original sources

PubMed2006

Compositional complementarity and prebiotic ecology in the origin of life.

We hypothesize that life began not with the first self-reproducing molecule or metabolic network, but as a prebiotic ecology of co-evolving populations of macromolecular aggregates (composomes). Each composome species had a particular molecular composition resulting from molecular complementarity among environmentally available prebiotic compounds. Natural selection acted on composomal species that varied in properties and functions such as stability, catalysis, fission, fusion and selective accumulation of molecules from solution. Fission permitted molecular replication based on composition rather than linear structure, while fusion created composomal variability. Catalytic functions provided additional chemical novelty resulting eventually in autocatalytic and mutually catalytic networks within composomal species. Composomal autocatalysis and interdependence allowed the Darwinian co-evolution of content and control (metabolism). The existence of chemical interfaces within complex composomes created linear templates upon which self-reproducing molecules (such as RNA) could be synthesized, permitting the evolution of informational replication by molecular templating. Mathematical and experimental tests are proposed.

Biological Evolution↗

PubMed2006

Antigenic complementarity in the origins of autoimmunity: a general theory illustrated with a case study of idiopathic thrombocytopenia purpura.

We describe a novel, testable theory of autoimmunity, outline novel predictions made by the theory, and illustrate its application to unravelling the possible causes of idiopathic thrombocytopenia purpura (ITP). Pairs of stereochemically complementary antigens induce complementary immune responses (antibody or T-cell) that create loss of regulation and civil war within the immune system itself. Antibodies attack antibodies creating circulating immune complexes; T-cells attack T-cells creating perivascular cuffing. This immunological civil war abrogates the self-nonself distinction. If at least one of the complementary antigens mimics a self antigen, then this unregulated immune response will target host tissues as well. Data demonstrating that complementary antigens are found in some animal models of autoimmunity and may be present in various human diseases, especially ITP, are reviewed. Specific mechanisms for preventing autoimmunity or suppressing existing autoimmunity are derived from the theory, and critical tests proposed. Finally, we argue that Koch's postulates are inadequate for establishing disease causation for multiple-antigen diseases and discuss the possibility that current research has failed to elucidate the causes of human autoimmune diseases because we are using the wrong criteria.

Amino Acid Sequence↗

PubMed2005

Antigenic complementarity between HIV and other AIDS-associated infections results in idiotype-antiidiotype antibody complexes that cross react with lymphocyte proteins.

HIV proteins mimic HLA proteins, and the proteins of cofactor infections (cytomegalovirus, hepatitis viruses, mycobacteria, mycoplasmas) mimic CD4 proteins, making some HIV antigens molecularly complementary to cofactor antigens. Antibodies to HIV and its cofactors should therefore act like idiotype-antiidiotype pairs. Over 2000 combinations of antibodies were tested for such complementarity using modified forms of Ouchterlony immunodiffusion and ELISA. HIV antibodies do precipitate some antibodies against cofactor infections including CMV, HBV, mycobacteria and mycoplasmas. These antibodies also mimic antibodies against HLA and CD4 proteins. Thus, some combinations of HIV with cofactor infections may induce lymphocytotoxic antibodies (LCTA), a risk that must be addressed in vaccine development.

AIDS-Related Opportunistic Infections↗

PubMed2004

Antigenic complementarity resulting in idiotype-antiidiotype immune complexes: possible contributor to AIDS pathogenesis and autoimmunity.

One hundred and sixty seven combinations of viral + viral antibodies or viral + bacterial antibodies were tested for their ability to precipitate each other. Some antibodies produced against HIV epitopes recognize and precipitate some antibodies produced against cytomegalovirus (CMV), hepatitis B virus (HBV) core antigen, and Mycobacteria tuberculosis (MTb) and Staphylococcus epitopes but not those against HBV surface antigen, herpes simplex types 1 and 2 (HSV1 and HSV2) or Epstein-Barr virus (EBV), Streptococcus, or Escherichia coli. In addition, CMV antibodies precipitate those of HBV core and surface antigens as well as MTb, but not HSV, HSV2, EBV, Streptococcus or E. coli. HBV core (but not surface) antibodies precipitated Mycobacterium avium antibodies (MAv) but not MTb, Streptococcus, Staphylococcus or E. coli antibodies. Binding constants vary between kds of 10(-9) and 10(-7) M. Interactive antibodies act like idiotype-antiidiotype pairs suggesting that the inducing antigens are molecularly complementary. The resulting antibody interactions may explain the formation of circulating immune complexes that are commonly found in AIDS and in other diseases characterized by multiple, concurrent infections. This observation suggests that AIDS pathogenesis may involve autoimmune mechanisms in which the immune system attacks itself to form antibody-antibody circulating immune complexes that contribute to the hypergammaglobulinemia characteristic of AIDS. Complementary cofactor infections in AIDS may therefore contribute to the immunosuppression of the syndrome and difficulties treating these corresponding infections.

Antibodies, Bacterial↗

PubMed2002

Molecular complementarity III. peptide complementarity as a basis for peptide receptor evolution: a bioinformatic case study of insulin, glucagon and gastrin.

Dwyer has suggested that peptide receptors evolved from self-aggregating peptides so that peptide receptors should incorporate regions of high homology with the peptide ligand. If one considers self-aggregation to be a particular manifestation of molecular complementarity in general, then it is possible to extend Dwyer's hypothesis to a broader set of peptides: complementary peptides that bind to each other. In the latter case, one would expect to find homologous copies of the complementary peptide in the receptor. Thirteen peptides, 10 of which are not known to self-aggregate (amylin, ACTH, LHRH, angiotensin II, atrial natriuretic peptide, somatostatin, oxytocin, neurotensin, vasopressin, and substance P), and three that are known to self-aggregate (insulin, glucagon, and gastrin), were chosen. In addition to being self-aggregating, insulin and glucagon are also known to bind to each other, making them a mutually complementary pair. All possible combinations of the 13 peptides and the extracellular regions of their receptors were investigated using bioinformatic tools (a total of 325 combinations). Multiple, statistically significant homologies were found for insulin in the insulin receptor; insulin in the glucagon receptor; glucagon in the glucagon receptor; glucagon in the insulin receptor; and gastrin in gastrin binding protein and its receptor. Most of these homologies are in regions or sequences known to contribute to receptor binding of the respective hormone. These results suggest that the Dwyer hypothesis for receptor evolution may be generalizable beyond self-aggregating to complementary peptides. The evolution of receptors may have been driven by small molecule complementarity augmented by modular evolutionary processes that left a "molecular paleontology" that is still evident in the genome today. This "paleontology" may allow identification of peptide receptor sites.

Computational Biology↗

PubMed2002

Are diabetic neuropathy, retinopathy and nephropathy caused by hyperglycemic exclusion of dehydroascorbate uptake by glucose transporters?

Vitamin C exists in two major forms. The charged form, ascorbic acid (AA), is taken up into cells via sodium-dependent facilitated transport. The uncharged form, dehydroascorbate (DHA), enters cells via glucose transporters (GLUT) and is then converted back to AA within these cells. Cell types such as certain endothelial and epithelial cells as well as neurons that are particularly prone to damage during diabetes tend to be those that appear to be dependent on GLUT transport of DHA rather than sodium-dependent AA uptake. We hypothesize that diabetic neuropathies, nephropathies and retinopathies develop in part by exclusion of DHA uptake by GLUT transporters when blood glucose levels rise above normal. AA plays a central role in the antioxidant defense system. Exclusion of DHA from cells by hyperglycemia would deprive the cells of the central antioxidant, worsening the hyperglycemia-induced oxidative stress level. Moreover, AA participates in many cellular oxidation-reduction reactions including hydroxylation of polypeptide lysine and proline residues and dopamine that are required for collagen production and metabolism and storage of catecholamines in neurons. Increase in the oxidative stress level and metabolic perturbations can be expected in any tissue or cell type that relies exclusively or mainly on GLUT for co-transport of glucose and DHA including neurons, epithelial cells, and vascular tissues. On the other hand, since DHA represents a significant proportion of total serum ascorbate, by increasing total plasma ascorbate concentrations during hyperglycemia, it should be possible to correct the increase in the oxidative stress level and metabolic perturbations, thereby sparing diabetic patients many of their complications.

Ascorbic Acid↗

PubMed2002

Mental tools for thinking about DNA technologies in new ways.

OBJECTIVE: To investigate the nature of creative thinking in biomedical science with specific applications to molecular pathologies and DNA technologies. DATA SOURCES: Accounts of breakthroughs and inventions contained in autobiographies, biographies, interviews, and archival sources. STUDY SELECTION: Discoveries that have altered, or may yet alter, basic textbook accounts of biomedical sciences for which appropriate data sources exist. DATA EXTRACTION: Approximately 1000 data sources were analyzed, both within appropriate sciences and in other creative fields, such as the arts. DATA SYNTHESIS: The current analysis is based on a framework described in our previous book, Sparks of Genius, which outlines a general approach to understanding creative thinking. CONCLUSIONS: Creative thinking in all disciplines depends on a common mental "toolkit" that consists of 13 fundamental tools: observing, imaging, abstracting, pattern recognition, pattern forming, analogizing, body thinking, empathizing, dimensional thinking, modeling, playing, transforming, and synthesizing. Scientists recognize and solve problems by observing data that break the patterns established by theories; exploring a system by creating an abstract model with which they can play; and transforming data into feelings, sounds, and other forms that create surprising analogies to already-understood principles. The result of such personal thinking is knowledge combined with sensation and emotion--feeling and understanding synthesized into complete awareness. We illustrate some of these modes of thinking with reference to recent breakthroughs in DNA-related areas and suggest ways in which the use of "tools for thinking" can increase the probability of making further discoveries in the biomedical sciences.

Biotechnology↗