Evidence Supports TSMT - Opposing Views

Evidence Supports TSMT

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The fact that animals are differently complex from humans explains why they have such little predictive value for human response to drugs and disease. The Theory of Evolution and Complexity Theory are the basis for Trans-Species Modeling Theory (TSMT). [1] TSMT predicts that more differences that affect drug and disease response will be found among species. Consider the following.

Diede et al state:

Genetic and epigenetic alterations are essential for the initiation and progression of human cancer. We previously reported that primary human medulloblastomas showed extensive cancer-specific CpG island DNA hypermethylation in critical developmental pathways. To determine whether genetically engineered mouse models (GEMMs) of medulloblastoma have comparable epigenetic changes, we assessed genome-wide DNA methylation in three mouse models of medulloblastoma. In contrast to human samples, very few loci with cancer-specific DNA hypermethylation were detected, and in almost all cases the degree of methylation was relatively modest compared with the dense hypermethylation in the human cancers. To determine if this finding was common to other GEMMs, we examined a Burkitt lymphoma and breast cancer model and did not detect promoter CpG island DNA hypermethylation, suggesting that human cancers and at least some GEMMs are fundamentally different with respect to this epigenetic modification. These findings provide an opportunity to both better understand the mechanism of aberrant DNA methylation in human cancer and construct better GEMMs to serve as preclinical platforms for therapy development. [2]

Mertens, et al. explain why nonsteroidal anti-inflammatory agents prevented Alzheimer’s disease in animal models but not humans:

Increasing evidence suggests that elevated Aβ42 fractions in the brain cause Alzheimer’s disease (AD). Although γ-secretase modulators (GSMs), including a set of nonsteroidal anti-inflammatory drugs (NSAIDs), were found to lower Aβ42 in various model systems, NSAID-based GSMs proved to be surprisingly inefficient in human clinical trials. Reasoning that the nonhuman and nonneuronal cells typically used in pharmaceutical compound validation might not adequately reflect the drug responses of human neurons, we used human pluripotent stem cell-derived neurons from AD patients and unaffected donors to explore the efficacy of NSAID-based γ-secretase modulation. We found that pharmaceutically relevant concentrations of these GSMs that are clearly efficacious in conventional nonneuronal cell models fail to elicit any effect on Aβ42/Aß40 ratios in human neurons. Our work reveals resistance of human neurons to NSAID-based γ-secretase modulation, highlighting the need to validate compound efficacy directly in the human cell type affected by the respective disease. [3]

Brüstle, one of the coauthors stated: “The results of our study are significant for future drug development approaches, because they imply that compound screening and validation studies might be much more reliable if they are conducted using the human cell type affected by the disease in question.” [4]Coauthor Mertens stated: “The results highlight the importance of testing compounds directly in authentic human cells.” Brüstle continues: “Until recently, it was difficult to obtain native human neurons for drug testing in the field of neurodegenerative diseases. With recent advances in iPSC technology, it has become possible to generate virtually unlimited numbers of human neurons from individual patients. We hope that our findings will promote the use of stem cell-derived neurons for drug screening in the field of neurological disorders.” [4]

The regulation of long interspersed element-1 (L1, also known as LINE-1) transposons in induced pluripotent stem cells differs between humans and apes. [5] This is a major difference with implications for why humans differ from apes.

Moreover, there are variations among humans and variations among human cells. Gallagher writes regarding the diversity of cancer cells from the same original cancer: “A single tumour can be made up of many separate cancers needing different treatments, say researchers.” [6] Potter et al. invented a new method of differentiating cells that led to this discovery. [7] This explains why some drugs fail to eliminate cancers. Gallagher states: “This process [of cancer] is chaotic and results in a ‘diverse’ tumour containing cancerous cells that have mutated in different ways.” Greaves states: “This has huge implications for medicine.”

More differences between ethnicities have ben discovered. The formation of blood clots differs between African Americans and European Americans. [8] The platelets from African Americans reacted more in response to thrombin. PAR4, a receptor involved in clotting, was specifically activated above what was expected. The scientists also discovered that the gene PCTP was expressed at higher levels in platelets from African Americans.

Scientists have also discovered variation in the genomes of neurons from the same human brain. [9]

TSMT states: “While trans-species extrapolation is possible when perturbations concern lower levels of organization or when studying morphology and function on the gross level, one evolved complex system will not be of predictive value for another when the perturbation affects higher levels of organization.” [1] The more science reveals regarding comparative medicine and personalized medicine, the more evidence we see that supports TSMT.

(Photo courtest of NASA and Wikepedia Commons http://en.wikipedia.org/wiki/File:Gravitational_lens-full.jpg)


1.         Greek, R. and L.A. Hansen, Questions regarding the predictive value of one evolved complex adaptive system for a second: exemplified by the SOD1 mouse Progress in Biophysics and Molecular Biology, 2013: p. http://dx.doi.org/10.1016/j.pbiomolbio.2013.06.002. http://www.sciencedirect.com/science/article/pii/S0079610713000539

2.         Diede, S.J., et al., Fundamental differences in promoter CpG island DNA hypermethylation between human cancer and genetically engineered mouse models of cancer. Epigenetics, 2013. 8(12): p. 1254-1260. http://www.landesbioscience.com/journals/epigenetics/article/26486/

3.         Mertens, J., et al., APP Processing in Human Pluripotent Stem Cell-Derived Neurons Is Resistant to NSAID-Based ≥-Secretase Modulation. Stem Cell Reports, 2013. http://linkinghub.elsevier.com/retrieve/pii/S2213671113001239

4.         Cell Press. New study explains why promising dementia drugs failed in clinical trials. 2013 December 5, 2013 [cited 2013 December 8]; Available from: http://www.eurekalert.org/pub_releases/2013-12/cp-nse120313.php.

5.         Marchetto, M.C., et al., Differential L1 regulation in pluripotent stem cells of humans and apes. Nature, 2013. 503(7477): p. 525-9. http://www.ncbi.nlm.nih.gov/pubmed/24153179

6.         Gallagher, J. Cancer diversity has 'huge implications'. 2013 Novermber 15, 2013 [cited 2013 December 8]; Available from: http://www.bbc.co.uk/news/health-24957089.

7.         Potter, N.E., et al., Single-cell mutational profiling and clonal phylogeny in cancer. Genome Res, 2013. http://www.ncbi.nlm.nih.gov/pubmed/24056532

8.         Edelstein, L.C., et al., Racial differences in human platelet PAR4 reactivity reflect expression of PCTP and miR-376c. Nat Med, 2013. 19(12): p. 1609-16. http://www.ncbi.nlm.nih.gov/pubmed/24216752

9.         McConnell, M.J., et al., Mosaic Copy Number Variation in Human Neurons. Science, 2013. 342(6158): p. 632-637. http://www.sciencemag.org/content/342/6158/632.abstracthttp://www.sciencemag.org/content/342/6158/632


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