Research using the worms Pristionchus pacificus and C. elegans has revealed that the same phenotype can come from different mechanisms. Vulval development appears to result in exactly the same outcome for both species but epidermal growth factor (EGF)–RAS pathway is the mechanism for C. elegans while P. pacificus uses WNT signaling. This is an example of developmental systems drift theory and demonstrates, again, that just because outcomes are similar or even the same, the mechanism underlying them may differ.(Burgess 2011; Wang and Sommer 2011) This different mechanism same oputcome is one of the problems with using animal models in drug and disease research. Affecting a specific mechanism in a mouse is not evidence that the same intervention will produce the same result in humans.
It is also an example of what can be learned using less complex organisms like worms and yeast. Fundamental processes like the above, can be learned or demonstrated in these organisms whereas discovering them in more complex organisms, like mice, could be challenging if not impossible. The level of organization where these processes occur, and the concepts they demonstrate, is not the same as for drug development and or disease research.
The level of organization that is relevant in drug development is where very small changes between complex systems can result in death or severe adverse side effects and why personalized medicine is so important. The breast cancer drug lapatinib causes severe liver damage in some patients. The susceptibility has been linked to genetic variants that can now be tested for.(Alfirevic and Pirmohamed 2011) Similarly, the epidermal growth factor receptor tyrosine kinase inhibitors erlotinib and gefitinib are more efficacious in patients with specific genetic mutations. More drugs are being developed for patients with similar mutations. (Dimou, Harrington, and Syrigos 2011)
Hudson states in the New England Journal of Medicine: “Genetic makeup can predict the occurrence of toxic effects, such as the hyper- sensitivity reaction that occurs in carriers of the HLA-B*5701 allele who receive abacavir for the treatment of human immunodeficiency virus infection. The presence of various mutations in tumors can also predict the efficacy of certain drugs, such as cetuximab and panitumumab for colorectal cancer, since tumors that contain certain somatic mutations in KRAS do not respond to these drugs. In addition, the findings of genomic research can be used to identify promising drug targets. Sequencing of genes encoding kinases led to the discovery of a BRAF mutation in melanoma, which in turn led to the development of PLX4032, a drug that was designed to inhibit the mutant BRAF protein and that brought about tumor regression in a majority of patients in a phase 1 clinical trial.”(Hudson 2011)
Dr Elizabeth Foot, Chief Executive Officer for London Genetics, wrote The path towards personalised medicine for Drug Discovery Today Editor’s Choice:
"With nearly every pharma company facing patent cliffs and the essential need to demonstrate cost-effectiveness, there has never been a more important time for the pharma industry to exploit and embrace the opportunities offered by our greater molecular understanding of disease pathophysiology and individual genetic variation. As reflected by the downloads included in this E-choice, to realise the full potential of new science requires the collaboration between all players including, although not limited to, academia, the pharmaceutical and biotechnology industries, regulatory authorities, payors and health economics. . . . Together these four articles highlight the progress made in pharmaogenetics and that indeed, although we are still at the start of realising its full potential, the promise of delivering novel, cost-effective drugs meeting patient unmet need, is already being achieved. With academia, industry, regulators, payors, health economics and the public working together, the next few years are undoubtedly going to be exciting and I envisage pharmacogenetics and personalised medicine becoming further embedded into mainstream clinical practice." (Foot 2011)
Contrast the above with the following is from Drug Discovery & Development October 03, 2011: "Over the next five years, National Institutes of Health (NIH) researchers will test and generate data about mice with disrupted genes to gain clues about human diseases thanks to a set of cooperative agreements totaling more than $110 million to begin the second phase of the Knockout Mouse Project (KOMP). . . . The project aims to enable the research community to establish traits associated with the function of every protein-coding gene in the mammalian genome. Such information will be valuable for the discovery of the genetic causes of human diseases and will aid efforts to identify new drug targets." (Drug Discovery & Development 2011)
Funding rodent research will not lead to personalized medicine.
Finally, when reading about the current Nobel Prizes in medicine or physiology, you might want to consider the following from one of the laureates. Ralph Steinman stated in 2002: “Patients have been too patient with basic research. Most of our best people work in lab animals, not people. But this has not resulted in cures or even significantly helped most patients.”(Steinman and Szalavitz 2002)
Alfirevic, A, and M Pirmohamed. 2011. Drug induced hypersensitivity and the HLA complex. Pharmaceuticals 4 (1):69-90.
Burgess, Darren J. 2011. Evo-devo: Hidden rewiring comes to light. Nat Rev Genet 12 (9):586-587.
Dimou, A., K. Harrington, and K. N. Syrigos. 2011. From the bench to bedside: biological and methodology considerations for the future of companion diagnostics in nonsmall cell lung cancer. Pathology research international 2011:312346.
Drug Discovery & Development. 2011. Disrupting Genes in Mice Gives Disease Clues. Drug Discovery & Development 2011 [cited October 4 2011]. Available from http://www.dddmag.com/Disrupting-Genes-inMice-Gives-Disease-Clues-100311.aspx?et_cid=2182275&et_rid=45518461&linkid=http%3a%2f%2fwww.dddmag.com%2fDisrupting-Genes-inMice-Gives-Disease-Clues-100311.aspx.
Foot, Elizabeth. 2011. The path towards personalised medicine. Drug Discovery Today, September 27 2011 [cited October 5 2011]. Available from http://www.drugdiscoverytoday.com/view/20989/the-path-towards-personalised-medicine/.
Hudson, Kathy L. 2011. Genomics, Health Care, and Society. New England Journal of Medicine 365 (11):1033-1041.
Steinman, RM, and M Szalavitz. 2002. Patients Have Been Too Patient With Basic Research. Cerebrum 4 (4).
Wang, Xiaoyue, and Ralf J. Sommer. 2011. Antagonism of LIN-17/Frizzled and LIN-18/Ryk in Nematode Vulva Induction Reveals Evolutionary Alterations in Core Developmental Pathways. PLoS Biol 9 (7):e1001110.