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Related Experiment Videos

Morphogenics as a tool for target discovery and drug development.

Nicholas C Nicolaides1, Wolfgang Ebel, Brad Kline

  • 1Morphotek Inc., Exton, PA 19342, USA. nicolaides@morphotek.com

Annals of the New York Academy of Sciences
|December 31, 2005
PubMed
Summary

Morphogenics, a platform process, generates genetic diversity by modulating DNA mismatch repair (MMR) genes. This approach accelerates drug discovery and the development of improved pharmaceuticals by creating varied cell phenotypes.

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Area of Science:

  • Genetics
  • Molecular Biology
  • Biotechnology

Background:

  • Mutations in DNA mismatch repair (MMR) genes cause genetic hypermutability.
  • Germline MMR gene mutations are linked to hereditary nonpolyposis colon cancer and other malignancies.
  • Modulating MMR (morphogenics) generates functional diversity through accumulated mutations.

Purpose of the Study:

  • To introduce morphogenics as a platform for generating genetic diversity.
  • To enable the development of pharmaceutical products and discovery of new targets.
  • To demonstrate the broad applicability and advantages of morphogenics.

Main Methods:

  • Employing a dominant negative MMR gene to induce random mutations (point and slippage).
  • Generating libraries of morphogenics-derived cells through mutagenesis.

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  • Screening cells in high-throughput assays for desired phenotypes.

    • Main Results:

    • Morphogenics successfully applied across diverse hosts (mammalian cells, mice, plants, yeast, bacteria).
    • Discovery of novel disease-associated phenotypes in model systems.
    • Generation of antibody-producing cell lines with enhanced binding affinities and titers.

    Conclusions:

    • Morphogenics is a versatile platform technology for creating genetic diversity.
    • It facilitates the discovery of druggable targets and novel pharmaceutical products.
    • Selective manipulation of MMR offers significant advantages in drug development and manufacturing.