David W. Martin

Abnormal Purine Metabolism and Purine Overproduction in a Patient Deficient in Purine Nucleoside Phosphorylase

To delineate the normal function of purine nucleoside phosphorylase and to understand the pathogenesis of the immune dysfunction associated with deficiency of this enzyme, we studied purine metabolism in a patient deficient in purine nucleoside phosphorylase, her erythrocytes and cultured fibroblasts. She exhibited severe hypouricemia and hypouricosuria but excreted excessive amounts of purines in her urine, the major components of which were inosine and guanosine. Her urine also contained deoxyinosine, deoxyguanosine and uric acid 9-N riboside. The patients erythrocytes but not her cultured fibroblasts contained increased concentrations of phosphoribosylpyrophosphate and inosine. The metabolic abnormalities resembled those in the erythrocytes of patients with the Lesch-Nyhan syndrome. Purine nucleoside phosphorylase is a necessary component of the major, if not the sole, pathway for the conversion of purine nucleosides and nucleotides to uric acid. The increased intracellular concentrations of inosine may, by inhibiting adenosine deaminase, be related to the immunologic dysfunction.

X-chromosome inactivation during differentiation of female teratocarcinoma stem cells in vitro.

Evidence is presented that both X chromosomes are genetically active in clonal cultures of undifferentiated female mouse teratocarcinoma stem cells derived from a spontaneous ovarian tumour. As the cells differentiate in vitro one of the X chromosomes becomes inactivated.

Cell-Cycle Dependent Variation in the Levels of Deoxyribonucleoside Triphosphate in Mouse T-Lymphoma Cells

De novo synthesis of deoxyribonucleotides occurs exclusively by the reduction of the corresponding ribonucleotides in a reaction catalyzed by the enzyme ribonucleotide reductase. The enzyme is subject to allosteric regulation in vitro and in vivo and its activity is closely correlated to the growth rate of cells. The changes in ribonucleotide reduction is correlated to changes in the measured deoxyribonucleoside triphosphate pools in a variety of cell lines but considerable variations in the relative levels of each of the four DNA precursors were found1.

Use of Teratocarcinoma Stem Cells as a Model System for the Study of X-Chromosome Inactivation In Vitro

One of the main obstacles to the study of the mechanism of X-chromosome differentiation or “X inactivation” is the difficulty of obtaining a population of embryonic cells in which both X chromosomes are functioning. The primary reason for this is that male embryos cannot be easily distinguished from female embryos, and therefore half of any random population of embryos will be males that contain only one X chromosome. Furthermore, since it is now apparent that X inactivation probably does not occur in all the cells of the embryo at the same time, there would be the additional difficulty of identifying and separating those cells in which both X chromosomes are active, even if a pure population of female embryos could be obtained. Since teratocarcinoma stem cells are closely similar to normal early embryonic cells and they are available in almost unlimited quantities, the goal of the research described here was to determine whether it might be possible to use clonal cultures of female teratocarcinoma stem cells, in place of embryonic cells, to study the phenomenon of X-chromosome inactivation. The results of this study have been described previously (Martin, Epstein, Travis, Tucker, Yatziv, Martin, Clift, and Cohen 1978).

Intravenous Deoxycytidine Therapy in a Patient with Adenosine Deaminase Deficiency

Adenosine deaminase (ADA) deficiency usually results in severe combined immunodeficiency disease. Without therapy, these children usually die from overwhelming infections. The most successful therapy remains bone marrow transplantation from a histocompatible sibling donor. Efforts at a biochemical approach have focused on enzyme replacement using repeated transfusions from ADA-positive donors (Polmar et al., 1976). Unfortunately, only a relatively few patients with ADA deficiency have histocompatible siblings to provide a bone marrow transplant and less than 50% of patients with ADA deficiency show a significant response to red cell transfusions. In addition, there are significant risks of repeated red cell transfusions, including iron overload, transfusion reactions, and viral infections.