Bioscope ‘04

by Dr. Barbara Price

Importance of Animal Models for Therapeutics

          In the early history of medical countermeasures, the research was often studies of how much of a chemical or biological agent would kill a group of animals. A medical countermeasure would be evaluated by giving the animals a drug and then measure its effectiveness because the combination (agent plus drug) either killed fewer animals or a higher concentration of the agent killed the same number of animals. The quality of the life of the survivors was often a footnote, if measured. The criteria for therapeutics are changing and the quality of the life of survivors is an important measure of the effectiveness of any medical treatment.

          Older data were LD50, LC50 etc. The biomarker was death. Later observation data include lesions in organs, onset and duration of seizures, carcinogenicity and changes in hormone production. In toxicology the NOAELs (no adverse effects levels) and LOAELs (lowest adverse effects levels) are now often determined, but even these are difficult to find. This has become especially important in environmental toxicology. With biological agents, we can measure the infectious dose, number of virions or organ damage. If we choose a more subtle biomarker than death, have we chosen an effect that is not reversible or is it a transient effect? If we choose organ lesions, what do the lesions mean? Biomarkers for observation or monitoring MAY be different than those for treatment. As we change the focus to studying how therapeutics work, we must change the biomarkers.

          In our search for medical treatments, whether for infectious or toxic chemical agent exposures, we need to understand and monitor all aspects of the pathogenesis of the agent. The treatment approaches are to deny the target (possibly to protect the receptor, such as in pyridostigmine bromide prophylaxis), remove or help to remove the agent, as with scavengers, or help the immune system to counter the agent, as with vaccines.

          In the body, the more subtle changes during the pathogenesis of chemical and biological agents occur at the cellular response. This is where DNA damage, protein expression, chemo- and cytokines variations and cell signaling occurs. If we are to develop and assess the performance of drugs we need to monitor and understand the changes in the chemokines and cytokines of the immune system. Our choices in animal models for an agent should have similar toxic responses, disease progression at the cellular and organ levels, and similar immune responses. An organism’s response to attack is a sequence of cell signals, which alert and initiate the immune response. The earlier in the attack we can intercept and assist the body, the fewer long term consequences there will be from either the agent, the drug or the treatment.