Animal Rights

Personalized Medicine Continues to Deliver

| by Dr Ray Greek

I often cite the development of personalized medicine in order to illustrate the lunacy of inter-species extrapolation of drugs and disease research. Because they cannot refute this, many vivisection activists simply dismiss personalized medicine as being futuristic or not viable. In its latest report, The Case for Personalized Medicine, the Personalized Medicine Coalition (PMC) documents the growth of commercially available personalized medicine products from 13 in 2006 to 72 currently. The report discusses various scenarios in which PM is currently used: "A patient has late-stage non-small cell lung cancer (NSCLC). She has gone through a number of treatments, but none were able to arrest the cancer’s spread. The mother of four has progressive disease and precious little time to waste on treatments that do not work. Her physician read reports of a newly approved drug called Xalkori® (crizotinib) that might offer hope. However, only about five percent of NSCLC patients whose tumors have the anaplastic lymphoma kinase (ALK) gene rearrangement can potentially benefit. A newly approved diagnostic test determines that the patient has the gene rearrangement and that the drug is a treatment option for her. After starting to take Xalkori®, the tumors begin to respond."[1]

A study published in PLoS Genetics revealed that small differences between the genes, called SNPs, of men and women result in large differences in the metabolism of drugs.[2] Sharp and Langer 2011: "The next challenge for biomedical research will be to solve problems of highly complex and integrated biological systems within the human body. Predictive models of these systems in either normal or disease states are beyond the capability of current knowledge and technology." [3]

The same science that explains why personalized medicine is necessary explains why inter-species extrapolation is not going to work. Even a minimal understanding of evolutionary biology and complexity science leads to the conclusion that the attempt to predict human response to drugs and disease by using another species is doomed to fail.

This is not to say that everything about animals and humans is different. Gross commonalities do exist. Recent research from the University of California - San Diego (UCSD) nicely illustrates this. Scientists performed MRI scans on 406 adult human twins and confirmed that the organization of the outer brain is generally the same among mammals and that the same genes are used in development. However, upon finer examination there were also differences. According to the press release: “For example, humans have very high-level thinking abilities. Mice don't engage in abstract thinking, but they do make extensive use of their whiskers to negotiate the sensory environment,” said William S. Kremen, PhD, professor of clinical psychology and corresponding author of the study. “Consistent with these species-specific features, we found that genetic influences resulted in greatly expanded frontal regions in humans – the area of the brain responsible for higher level functions – but much-expanded somatosensory regions in the mouse brain.” The article is in the November 17 issue of the journal Neuron.

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This is exactly what we would expect based on current understanding of evo devo and evolution in general. The same set of mammal genes can be used to make just about any mammal. The inter-species differences being due to the regulation and expression of those genes. Of course, there are other differences among species because of a small number of different genes being in mammal A as opposed to mammal B. Overall however, the same genes can build most any mammal (more or less). Moreover, the general architecture is the same. The heart and liver are more or less the same shape across species lines, as is the brain. Nevertheless, the function of these organs varies dramatically in terms of metabolizing drugs and susceptibility to disease.

A study published in Mobile DNA [4] reveals that junk DNA may be the defining difference between humans and chimpanzees. Transposable elements are thought to be important in gene regulation. John F McDonald, study leader, stated: “Our findings are generally consistent with the notion that the morphological and behavioral differences between humans and chimpanzees are predominately due to differences in the regulation of genes rather than to differences in the sequence of the genes themselves.”[5]

By studying humans, scientists were able to link the gene to the development of the pancreas. Pancreatic agenesis is rare but a mutation in the gene GATA6 was discovered in patients with the disorder. GATA6 has been studied in mice who apparently do not need the gene in order to develop a normal pancreas. [6, 7]

Accepting that there are inter- and intra-species variations is important when designing research and evaluating treatments but so is an appreciation of intra-individual variation. Pre-exposure prophylaxis (PrEP) for HIV has not been 100% successful. Scientist studied humans in order to evaluate tissue levels for the PrEP drugs tenofovir (TFV) and emtricitabine (FTC). The tissues studied were from the lining of the vagina, cervix and rectum. They discovered the concentration of TFV were 100 times greater in tissues from the rectum than the vagina and cervix. Conversely, FTC concentrations were 10-15 times greater in the cervix and vagina than the rectum.[8, 9] This has important implications for prescribing PrEP as well as other drugs.

Human-based research will continue to make personalized medicine a reality for more and more patients. If it gets funded. (For more on personalized medicine and animal models see our latest article available here.[10])

References

1.         The Case for Personalized Medicine [http://www.personalizedmedicinecoalition.org/sites/default/files/files/Case_for_PM_3rd_edition.pdf]

2.         Mittelstrass K, Ried JS, Yu Z, Krumsiek J, Gieger C, Prehn C, Roemisch-Margl W, Polonikov A, Peters A, Theis FJ, et al: Discovery of sexual dimorphisms in metabolic and genetic biomarkers. PLoS genetics 2011, 7:e1002215.

3.         Sharp PA, Langer R: Promoting Convergence in Biomedical Science. Science 2011, 333:527.

4.         Polavarapu N, Arora G, Mittal VK, McDonald JF: Characterization and potential functional significance of human-chimpanzee large INDEL variation. Mobile DNA 2011, 2:13.

5.         "Junk DNA" defines differences between humans and chimps [http://gatech.edu/newsroom/release.html?nid=71798]

6.         Allen HL, Flanagan SE, Shaw-Smith C, De Franco E, Akerman I, Caswell R, Ferrer J, Hattersley AT, Ellard S: GATA6 haploinsufficiency causes pancreatic agenesis in humans. Nat Genet 2011, advance online publication.

7.         Rare genetic disorder provides clues to development of the pancreas [http://www.sciencedaily.com/releases/2011/12/111211133958.htm]

8.         Patterson KB, Prince HA, Kraft E, Jenkins AJ, Shaheen NJ, Rooney JF, Cohen MS, Kashuba ADM: Penetration of Tenofovir and Emtricitabine in Mucosal Tissues: Implications for Prevention of HIV-1 Transmission. Science Translational Medicine 2011, 3:112re114.

9.         Kashuba ADM, Patterson KB, Dumond JB, Cohen MS: Pre-exposure prophylaxis for HIV prevention: how to predict success. The Lancet 2011.

10.       Greek, Ray, Andre Menache, and Mark J. Rice. 2012. Animal models in an age of personalized medicine. Personalized Medicine 9 (1):47-64.