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What are the alternatives to using mice and other animals in scientific research?

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Muhammad M Rahman
Muhammad M Rahman Feb 09, 2021

[1]Berning M, Prätzel-Wunder S, Bickenbach JR, Boukamp P. Three-Dimensional In Vitro Skin and Skin Cancer Models Based on Human Fibroblast-Derived Matrix. Tissue Eng Part C Methods. 2015 Sep;21(9):958-70. doi: 10.1089/ten.TEC.2014.0698. Epub 2015 May 7. PMID: 25837604.

[2]Kolodka TM, Garlick JA, Taichman LB. Evidence for keratinocyte stem cells in vitro: long term engraftment and persistence of transgene expression from retrovirus-transduced keratinocytes. Proc Natl Acad Sci U S A. 1998 Apr 14;95(8):4356-61. doi: 10.1073/pnas.95.8.4356. PMID: 9539741; PMCID: PMC22493.

[3]Ojeh N, Akgül B, Tomic-Canic M, Philpott M, Navsaria H. In vitro skin models to study epithelial regeneration from the hair follicle. PLoS One. 2017 Mar 28;12(3):e0174389. doi: 10.1371/journal.pone.0174389. PMID: 28350869; PMCID: PMC5370106.

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Computer (in silico) modeling

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Shubhankar Kulkarni
Shubhankar Kulkarni Feb 09, 2021

[1]Martonen T, Fleming J, Schroeter J, Conway J, Hwang D. In silico modeling of asthma. Adv Drug Deliv Rev. 2003 Jul 18;55(7):829-49. doi: 10.1016/s0169-409x(03)00080-2. PMID: 12842603.

[2]https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/quantitative-structure-activity-relationship#:~:text=Third%20Edition)%2C%202014-,QSAR,back%20to%20the%20nineteenth%20century.

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Muhammad M Rahman
Muhammad M Rahman20 days ago
This is the way that a lot of research is heading with a focus on bioinformatics and machine learning however, there has to be validation using cellular systems. One thing to consider is that when you add drugs to cells, you get different responses based on the cell type and even the sub-population i.e. the stem cell may not respond like differentiating cells. If you then try and simulate cancer cell response you have to factor in the multiple mutations for those cells and also consider compensatory mechanisms that often make such drugs less effective than what was originally expected. The question then is which lab based cancer models could be used to test drugs.
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Shubhankar Kulkarni
Shubhankar Kulkarni20 days ago
Muhammad M Rahman I agree. We still need animal models for validating the results. However, the in silico models have reduced the dependency on animal models. Drug interactions can be studied in silico and only a few selected important interactions can be validated in the animals. This reduces the use of animal models. Moreover, the range of the magnitude of effects that you can choose in the in silico models far exceeds that of the real physiology and hence, the kind of effect that is possible in the in silico models may or may not be observed in the animal models but the effects that are not possible in the in silico models are impossible in the real scenario, too. This gives you an idea of the upper and lower limits of an effect in real physiology. So the in silico models help in there, too. If the observations from real life are beyond those that the model could predict, you know you are missing a crucial property from real data and need to add that to the model.

I agree that each cancer cell might have a different set of mutations. So, when you try to mimic them in silico, you need to set a probability of a cell having a mutation close to random. You can also set the type of mutation as random. So, basically, you start with the most random cancer cell design. Then you start tweaking the parameters as per the observations from human patients. For example, if colorectal carcinoma cells show a high probability of mutations that lead to the overexpression of TWIST1 (a transcription factor), you add that observation to your model. So, when you attach a random probability to all other mutations, you attach a higher probability to the TWIST1 overexpression mutants, which will be based on the proportion of observed TWIST1 mutations out of all the mutations observed in real data. This takes your model closer to the real one and the results from your model are, therefore, robust.

There is no limit to how closely you can mimic a cancer cell/ tumor; so you need to decide the level of complexity (adding more real-life parameters makes your model more and more complex) you want in your model depending upon the kind of questions you want to answer. For example, if you simply want to identify the range of the kind of mutations that are observed in breast cancer, a random cancer model with an initial set of epigenetic modifications observed in healthy breast tissue and a few major mutations to start with (like BRCA1 mutations) will suffice. On the other hand, most researchers consider colorectal cancer as a single unit. However, if you want to differentiate how colon cancer and rectal cancer will react to a certain drug, you may want the cancer cell models to precisely mimic colon and rectal cancers separately. Although both these cancers have minute differences, they may behave differently to a certain new drug; after all, their locations are different.

Human-patient simulators

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Shubhankar Kulkarni
Shubhankar Kulkarni Feb 09, 2021

[1]https://caehealthcare.com/patient-simulation/

[2]https://www.peta.org/blog/countries-end-animal-labs-traumaman/

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Muhammad M Rahman
Muhammad M Rahman20 days ago
Excellent find, these models have helped in the advancement of medical training methods but as you have mentioned, the costs are very high.
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Manel Lladó Santaeularia
Manel Lladó Santaeularia21 days ago
That's fascinating. I wonder what is the cost of this kind of equipment however. A big step in making a significant change in the use of animal models would be to make this kind of simulators available in most hospitals/med schools and I imagine that could be an issue.

I also wonder, what about anatomical variation, for example? Anyone who was studied practical anatomy knows very well that organs, veins, nerves and such are not always the same in terms of shape, size and position. Do these simulators account for that, so that students can learn practicing with different situations?
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Shubhankar Kulkarni
Shubhankar Kulkarni21 days ago
Manel Lladó Santaeularia I know, right! The prices are somewhere between USD 40k and 45k. (https://savvik.com/wp-content/uploads/2019/05/CAE-Healthcare-Pricing.pdf). According to this article (https://www.peta.org/blog/countries-end-animal-labs-traumaman/), more and more institutions are opting for the stimulators. They are widely used in medical schools and hospitals. I did not find anything on the anatomical variation in the products. However, I imagine there will be close to zero variation, since, it will increase the cost of each simulator.

What about the ethical considerations?

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Muhammad M Rahman
Muhammad M Rahman Feb 13, 2021

Research using human volunteers

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Shubhankar Kulkarni
Shubhankar Kulkarni Feb 09, 2021

[1]https://www.peta.org/issues/animals-used-for-experimentation/alternatives-animal-testing/#:~:text=These%20alternatives%20to%20animal%20testing,and%20studies%20with%20human%20volunteers.

Why animal models are necessary (so far)

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Manel Lladó Santaeularia
Manel Lladó Santaeularia Feb 09, 2021

[1]Winkler PA, Occelli LM, Petersen-Jones SM. Large Animal Models of Inherited Retinal Degenerations: A Review. Cells. 2020;9(4):882. Published 2020 Apr 3. doi:10.3390/cells9040882

[2]Colella P, Ronzitti G, Mingozzi F. Emerging Issues in AAV-Mediated In Vivo Gene Therapy. Mol Ther Methods Clin Dev. 2017 Dec 1;8:87-104. doi: 10.1016/j.omtm.2017.11.007. PMID: 29326962; PMCID: PMC5758940.

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Muhammad M Rahman
Muhammad M Rahman20 days ago
Excellent points, thank you. Yes, it is near impossible to develop artificial models for to account for behaviour. I would also add that with animal models, long term tests can take place for months and even years which is currently not possible with any artificial model. However, with organ on a chip models developing, it is not beyond our reach to create models for a number of organs and somehow integrate them as one larger system.
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Shubhankar Kulkarni
Shubhankar Kulkarni21 days ago
All important points Manel Lladó Santaeularia ! I would like to stress the point of exposing unwanted and dangerous effects using animal models. In vivo experiments are useful to track the effects of a drug throughout the body of the organism. If a drug that is supposed to be good for the heart, in some way, damages the kidneys, then such an effect would not be observed in in vitro cell or even organ studies and may or may not be observed using the computational models. Moreover, animal behavior is intricately connected to their physiology. Every aspect of the behavior has some effects or causes in physiology. Studying the behavior, therefore, is also a good proxy for the changes happening inside the organism.
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Manel Lladó Santaeularia
Manel Lladó Santaeularia20 days ago
Shubhankar Kulkarni Great point. Behavior is clearly not something that can be easily modelled because it comes from the interaction of the mind and the physiology, and thus is extremely complex and unpredictable. That is the field that I believe will take the longest to see significant substitution of animal experimentation.

However, the more we know about the different organs (i.e. cell receptors, physiology) and the mechanisms of action of drugs themselves, the easier it will be to generate in silico models that can accurately predict more and more the effects of drugs on different parts of the human body. The difficulty will probably fall into being able to integrate all of those models of different organs or different effects into one, which would immensely facilitate this kind of study (imagine having to run a simulation for each organ or for each compound of your drug). And still, this should go to extensive iteration (which would regardless need some animal experimentation to confirm the results obtained by the artificial intelligence) and would probably take a very long time. However, it would be worth it in the long term, especially because this kind of in silico model could probably mimick the human body in a way that other organisms are unable to, considering some of the differences I have already mentioned.

Clearly the most important thing in order to achieve something like that is to collect as much information as possible, from a biochemichal, molecular, physiological and clinical standpoint, and find a way to integrate and convert all this information into a proper model. Any voluntary brilliant minds?

The Digital Twin concept

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Manel Lladó Santaeularia
Manel Lladó Santaeularia Feb 09, 2021

[1]Alber M, Buganza Tepole A, Cannon WR, et al. Integrating machine learning and multiscale modeling-perspectives, challenges, and opportunities in the biological, biomedical, and behavioral sciences. NPJ Digit Med. 2019;2:115. Published 2019 Nov 25. doi:10.1038/s41746-019-0193-y

[2]Bruynseels K, Santoni de Sio F, van den Hoven J. Digital Twins in Health Care: Ethical Implications of an Emerging Engineering Paradigm. Front Genet. 2018;9:31. Published 2018 Feb 13. doi:10.3389/fgene.2018.00031

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Muhammad M Rahman
Muhammad M Rahman20 days ago
You mention personalised treatment and that does exist in individual patient RNA sequencing whereby you might take a tumour biopsy of a patient along with normal tissue then run identify mutations in the individual. Furthermore, if biopsy tissue is cultured and directly tested with drugs then you treat the patient with drugs that you know work with the patient cells. This technology is here now but it’s expensive and not feasible. The Digital Twin model I believe will become a great resource but it depends on the richness of data. By that I mean that I would like to know how my biology compares to other people in my demographic whether that is ethnicity, height, weight, economic status and anything that may affect an individual’s health. To gather this type of information raises ethical issues with data collection and the potential conclusions that could be made.

Making humans in the lab on microchips?

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Muhammad M Rahman
Muhammad M Rahman Feb 10, 2021

[1]1. Zhang, B. et al. (2018) Advances in organ-on-a-chip engineering. Nat. Rev. Mater. 3, 257–278

[2]2. Xia, Y. and Whitesides, G.M. (1998) Soft lithography. Angew. Chem. Int. Ed. Eng. 37, 550–575

[3]3. Duffy, D.C. et al. (1998) Rapid prototyping of microfluidic systems in poly(dimethylsiloxane). Anal. Chem. 70, 4974–4984

[4]4. Whitesides, G.M. (2006) The origins and the future of microfluidics. Nature 442, 368–373

[5]5. Bhatia, S.N. and Ingber, D.E. (2014) Microfluidic organs-on chips. Nat. Biotechnol. 32, 760–772

[6]6. Wevers, N.R. et al. (2018) A perfused human blood-brain barrier on-a-chip for high-throughput assessment of barrier function and antibody transport. Fluids Barriers CNS 15, 23

[7]7. Marturano-Kruik, A. et al. (2018) Human bone perivascular niche-on-a-chip for studying metastatic colonization. Proc. Natl. Acad. Sci. U. S. A. 115, 1256–1261

[8]8. Shim, K.Y. et al. (2017) Microfluidic gut-on-a-chip with three dimensional villi structure. Biomed. Microdevices 19, 37

[9]9. Ma, C. et al. (2016) On-chip construction of liver lobule-like microtissue and its application for adverse drug reaction assay. Anal. Chem. 88, 1719–1727

[10]10. Shik Mun, K. et al. (2019) Patient-derived pancreas-on-a-chip to model cystic fibrosis-related disorders. Nat. Commun. 10, 3124

[11]11. Ahn, S. et al. (2018) Mussel-inspired 3D fiber scaffolds for heart-on-a-chip toxicity studies of engineered nanomaterials. Anal. Bioanal. Chem. 410, 6141–6154

[12]12. Miller, P.G. and Shuler, M.L. (2016) Design and demonstration of a pump less 14 compartment microphysiological system. Biotechnol. Bioeng. 113, 2213–2227

[13]13. Van Norman, G.A. (2019) Limitations of animal studies for predicting toxicity in clinical trials: is it time to rethink our current approach? JACC Basic Transl. Sci. 4, 845–854

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Shubhankar Kulkarni
Shubhankar Kulkarni20 days ago
Great! This would certainly help reduce the number of animal experiments.

To extrapolate the idea further, we can combine the Digit Twin and this human-on-a-chip concept. What if we could develop organs that specifically mimic a person's organs? The DNA from the patient can be extracted and a human-on-a-chip can be constructed out of it. This will take us another step closer to treating the patient by targetting their own organs on the chips.

If human-on-a-chip is feasible, so will this idea be. There might be ethical issues though, I don't know. Also, how much time does it take to develop an organ on a chip? If there is a patient who needs medical treatment in a span of months, the organ construction should be achieved way before that.

3D hair follicle models

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Muhammad M Rahman
Muhammad M Rahman Feb 19, 2021

[1]Higgins CA, Richardson GD, Ferdinando D, Westgate GE, Jahoda CA. Modelling the hair follicle dermal papilla using spheroid cell cultures. Exp Dermatol. 2010 Jun;19(6):546-8. doi: 10.1111/j.1600-0625.2009.01007.x. Epub 2010 Apr 20. PMID: 20456497.

[2]Castro AR, Logarinho E. Tissue engineering strategies for human hair follicle regeneration: How far from a hairy goal? Stem Cells Transl Med. 2020 Mar;9(3):342-350. doi: 10.1002/sctm.19-0301. Epub 2019 Dec 26. PMID: 31876379; PMCID: PMC7031632.

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