Our Science – Kohn Website
Kurt W. Kohn, M.D., Ph.D.
During this time (1961-1997), Kohn's major area of investigation concerned the mechanisms of action of DNA-targeted anticancer drugs. He demonstrated that bifunctional alkylating agents produce DNA interstrand crosslinks and that this is their major cytotoxic action. He elucidated a new mechanism of drug action on DNA, based on the anthramycin group of antibiotics. In 1974, he discovered the DNA filter elution phenomenon in which DNA molecules pass through micropore filters at a rate dependent on DNA strand length. Based on these observations, he developed methodology to measure several types of DNA damage in mammalian cells. This methodology was widely used for more than 20 years in many laboratories to study DNA damage and repair in mammalian cells. By DNA filter elution studies, Kohn and his colleagues in 1979-1982 showed that DNA topoisomerases are targets of action of several clinical anticancer drugs. This led to worldwide interest in topoisomerase-targeted drugs that has continued to the present time. In the 1990's, Kohn and his colleagues began to apply the emerging knowledge of cell cycle checkpoints to study the responses of cancer cells to DNA damage. As an aid to this end, Kohn developed a notation for molecular interaction maps that has recently received considerable interest.
Since 1997, Kohn has continued as a Principle Investigator in the LMP, focusing on molecular interaction mapping and computer simulation of bioregulatory networks relevant to cancer and therapeutics. In addition, he continues to collaborate and consult on various LMP projects and with other laboratories.
Molecular interaction maps
To best apply the emerging biomolecular information to new therapies, vast amounts of information must be organized in a functionally meaningful manner. The equivalent of electronic circuit diagrams are needed by which functional pathways can be traced conveniently and unambiguously, showing the molecular details as well as the network logic. Preparation of useful maps of bioregulatory networks however is difficult because of the extensive protein-protein interaction and protein modifications that characterize these systems. Additional difficulties are posed by interactions at membranes, transport between cell compartments, gene regulation, and interactions between domains within the same protein molecule. Moreover, to be of practical value a map should avoid representing the same component (such as a given protein) in more than one place. To meet these challenges, a convention for molecular interaction maps was proposed, and was shown capable of representing a variety of complex bioregulatory networks (Kohn, 1999; Kohn, 2001).
Kohn and his colleagues are preparing detailed molecular interaction maps of the networks that regulate cell proliferation and programmed cell death (apoptosis). The information for these maps is gleaned from the recent scientific literature. The maps are annotated with salient information and references, and are linked to other databases. This organizes a huge amount of information about the molecular regulatory networks. The maps are used to show the consequences of deletion or defects of particular components of the network, or of drug-induced inhibition of particular pathways.
In addition to detailed molecular interaction maps, the group is preparing logic summary diagrams of these systems, which will eventually be combined into an overall schematic.
Computer simulation of bioregulatory network behavior
To comprehend the functional capabilities of complex networks, computer simulation is necessary. Kohn and colleagues carry out such studies using software he has developed specifically for simulations based on molecular interaction maps. Simulation studies have been published of cell cycle control by E2F and pRb (Kohn 1998) and of the cell's responses to hypoxia (Kohn et al. 2004). Current work aims to use computer simulations to reveal the functional capabilities of the network centered on tumor suppressor protein p53.
This page was last updated on 3/31/2014.