Genetics-Based Study for Evaluating Drug P Response and Drug D Treatment

1. The gene for metabolic enzyme M1 is involved in catabolism of Drug P. The structurally-related drug Drug D is metabolized by a metabolic enzyme M2. Suppose that you wanted to initiate a genetics-based study to evaluate which patients would best be treated with Drug P, and for whom it would be better to use the related agent Drug D. In this question we will assume that ultrarapid metabolism (by either enzyme) confers a poor prognosis for response. Describe everything that you might do to complete this study*, such that it could be submitted to a scientific journal for review. Your answer should include

(1) What is the specific goal of the study (i.e. state what specifically will be determined);

(2) Description of several experiments (more than 1 and no more than 5), including how you would obtain data, and present their results.

(3) Conclusions about pharmacogenetic guidance, based on your study. Aim to tie everything together in a logical way. (Would this be a pharmacogenetic or pharmacogenomic study?)

(It’s difficult to guide you in exactly how you should write this. For example, you should cite specific kinds of studies and approaches, and what they measure, but you don’t need to go through the detail of how that is done. If, for example, any part of your answer involved sequencing, it is sufficient to merely say “I would sequence …” (Please don’t write any details beyond this sort of general statement of approach. However, you should be precise; in this example, that might mean precisely saying exactly what would be sequenced)) 

The disease malaria is caused by the microorganism Plasmodium falciparum and is transmitted by the Anopheles mosquito, and is one of the 3 major infectious disease killers of the modern world. New therapies to target malaria are being actively investigated. One strategy is to target the insect that transmits the disease.

You decide to focus on the gene encoding heat shock protein 90 (hsp90) as an attractive new drug target.

(1) Describe how you would go about cloning the gene for hsp90 from Anopheles. Include all steps necessary for a reader to evaluate whether your proposed procedure would be successful—but no need to include trivial issues such as, for example, how to make DNA segments that might used (one can just buy them) or how to sequence DNA (one can just have a company do it for you). 

(2) How would you conclusively establish at the end of your procedure that the cloned gene was Hsp90?

(3) How could you use the cloned gene to improve human health through drug therapy?

Tasmanian devils (a dog-like creature) have recently begun to suffer from a disease that causes them to develop infectious transmissible facial tumors. The number of Tasmanian devils is dramatically declining because of this, and though there are still hundreds of thousands, there are worries that they may become extinct. (this part is accurate. What follows is an imagined (not real) scenario so don’t be searching for clues)

However, it has been observed that there is a relatively large population of Tasmanian devils in the western part of Tasmania with significant inherent resistance to the disease, suggesting that individuals within this local, geographically-isolated population may share genetic features that render them less susceptible to infections that can produce the tumors.

(1) Describe how you would carry out a GWAS study to identify the gene(s) (gene variants) found in Tasmanian devils living in western Tasmania that confers resistance to infection to them. What would be one limitation that might be encountered in achieving an unambiguous discovery? (related to pharmacogenetic studies; please do not answer something like “they would be too difficult to catch” or “I would contract the disease”; I’m looking for a statement(s) like one might read in a scholarly journal relating to a pharmacogenetics study).

(2) Describe how this study in Tasmanian Devils might be applicable to human health and drug development.