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So What is Humanization?

Summary

Humanized animal models are becoming more widely used as new gene editing techniques become available and there is a push for a more personalized approach to medicine, but what exactly is humanization? In this article we discuss the history, the types of humanized models, and how they can be applied to your research. 

The idea of cross-species transplantation may sound like something out of a science fiction movie, but it isn’t a new concept. Looking back at ancient mythology it is common to see representations of physical features merging across species (for example – the centaur). The first documented clinical experiments, however, were in the 17th century when Jean Baptiste Denis transfused blood from animals into humans (Cooper, Esker & Tector, 2015). World War Two is considered a turning point for transplantation, as there was a push for the ability to perform allotransplants, or human-to-human transplants which led to the modern field of transplantation (Tobin et al., 2009). After several hundred years of experimenting this new kind of clinical transplantation was successfully performed in 1954. Now, over sixty years later, new gene editing techniques have enabled researchers to create ‘humanized xenografts’ which is a model organism that has been injected with human genes of interest. Humanized animal models have been called the next generation of models because they are an incredibly powerful tool that can be used for experiments which may be  unethical or difficult to perform in human patients, but produce results with higher validity than traditional animal models.

humanization

Types

There are two types of Humanized models: Whole Gene Humanized models and Point Mutation Humanized models. Whole Gene Humanization consists of replacing an animal’s gene for the human sequence; this full replacement of the ortholog locus results in a highly accurate model of a human which is particularly useful for drug screens. On the other hand, Point Mutation Humanization only deals with one ‘point’, a single amino acid, by inserting the human clinical variant into the animal gene. Point Mutation Humanization only works if sequence conservation is high, however it is faster and more cost effective than Whole Gene Humanization. Therefore, when you are designing your experiment, which type of humanization technique should be considered. 

Traditionally, humanization technology has been limited to the creation of mice models, however, alternative model organisms such as zebrafish and C. elegans offer cheaper models that are able to be developed faster. Furthermore, these non-mammalian models have significant advantages, such as their transparency which makes them excellent models for in vivo imaging. 

Applying Humanized Models

Once the model organism has undergone gene editing, becoming ‘humanized’ to include a clinical variation, these models are known as ‘human avatars’. These models have the potential to accelerate personalised medicine, because “it’s like having a bit of the patient inside the animal” (Dr Rita Fior, 17 Minutes of Science Episode 37). Using these models, genetic mutations can be better understood, drugs can be screened, and therapies can be more accurately tested prior to clinical trials, all at a faster pace than with traditional methods. 

Humanized models provide promising avenues for many areas of research: for instance, rare diseases (identifying variants of uncertain significance), regenerative cellular therapies and cancer research (taking from a patient tumor and inserting into a model, allowing researchers to screen), and drug discovery. There have already been exciting success stories using humanized models, such as tackling the congenital disorder PMM2. This drug repurposing project is known as Maggie’s Cure, and is exemplary of how a Point Mutation Humanized model can greatly advance personalized medicine.  

Conclusion

Humanized models are just at the beginning of their potential, as more areas of research adopt humanized models, and different model organisms are used. Like any model organism, it is important to understand the advantages of limitations of the different types so that they can best be applied to your research. Overall, humanized models are animal models that provide a clear picture of the nature and pathogenesis of human-specific pathogens and variants.

References

  1. Cooper, D., Ekser, B., & Tector, A. J. (2015). A brief history of clinical xenotransplantation. International journal of surgery (London, England), 23(Pt B), 205-210. https://doi.org/10.1016/j.ijsu.2015.06.060
  2. Tobin, G. R., Breidenbach, W. C., 3rd, Ildstad, S. T., Marvin, M. M., Buell, J. F., & Ravindra, K. V. (2009). The history of human composite tissue allotransplantation. Transplantation proceedings, 41(2), 466-471. https://doi.org/10.1016/j.transproceed.2009.01.026

About The Author

Alexandra Narin

Alexandra is the Marketing Content Manager and Grant Writer for InVivo Biosystems. She graduated from the University of St Andrews in 2020 where she earned a Joint MA Honours Degree in English & Psychology/Neuroscience with BPS [British Psychology Society] Accreditation. She has worked as a research assistant, examining the LEC's (lateral entorhinal cortex) involvement in spatial memory and integrating long term multimodal item-context associations, and completed her dissertation on how the number and kinds of sensory cues affect memory persistence across timescales. Her hobbies include running, boxing, and reading.

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