Clone selection theory

Long before any immunoglobulins had been sequenced, Burnet (1959) proposed his clone selection theory. Soluble antibodies are produced by mature lymphocytes. Burnet proposed that undifferentiated stem cells, which mature into antibody-secreting cells, are initially pluripotent and potentially able to produce a wide variety of antibodies. During the cell divisions that lead to their maturation, they become unipotent, i.e. each cell produces only one type of... 

A key feature of the clonal selection theory is that each antibody-forming cell or clone is committed to the expression of one antibody. The diversity in the response is a consequence of the great variety of distinct clones. Initially, Burnet (1957) assumed that antibody diversification occurs exclusively early in life, by a random... 

The clonal selection theory of Burnet (2) is now generally accepted. Small lymphocytes are known to have immunoglobulin receptors which are similar or identical to the antibodies that will later be synthesized by descendants of a cell. The receptors are believed to be produced initially without input of information from the antigen. The role of antigen is to combine with the receptors, thereby stimulating the differentiation and repeated cell division that results in the formation of a clone of cells, all producing the same antibody molecule. (The possibility of a switch within a cell, with respect to class of immunoglobulin produced, will be considered later.)... 

The clonal selection theory implies that the B-lymphocytes do not use antigenic information to construct antibodies but that the amino acid sequences of the antigen-binding sites are inherent in the genome. The production of genes that can code for millions of different antibodies, only a few of which are ever used, seems an extremely wasteful process. However, the random generation of different patterns or variations, only some of which are selected, is the basis of Darwin s theory of evolution, and antibody production by a clone descended from one stimulated lymphocyte is an example of the survival of the fittest . 

Under certain conditions, the Gompertzian tumor model provides an accurate barometer for tumor growth in vivo. However, deviations occur over time due to selection and expansion sub-clones that are chemo-resistant. Skipper s Cell Kill Hypothesis is based on the notion that chemotherapy will lead first-order cell kill kinetics. Therefore, each administration of chemotherapy will produce tiie same fraction of tumor cell death. In theory, it is believed that a log-cell drop of 9 to 11 orders of magnitude is required for tumor eradication. Clinically this scenario is complicated by the chemosen-sitivity of normal tissue and tumor, pharmacokinetic hetereogeneity of patients, and tumor heterogeneity. 

In our laboratory we have been using M2 seed families and mutagenized haploid protoplasts of Nicotianaplumbaginifolia in a combined approach to search both for mutants resistant to toxic concentrations of auxins and cytokinins, and for temperature-sensitive auxin auxotrophs. The hope has been that variation isolated using these rather unspecific selection procedures would include mutations in hormone uptake, biosynthesis, catabolism and reception. The isolation methods, particularly for the cloning of auxotrophs, are laborious, and during the last five years we have slowly assembled a small collection of mutants which we feel will allow us to test several current theories about auxin and cytokinin synthesis and mode of action. This paper briefly reviews our work on the mutants and their characterization. 

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