Ask a Scientist: Humanized Mice vs. Conventional Mice

In drug development, animal testing usually starts with a mouse model. What kind of model depends upon the questions the researcher is asking.

Mice have long served as a preferred species for biomedical research in the preclinical realm due to their anatomical, physiological, and genetic similarity to humans. Take cancer research for example. In the nearly 50 years since the original models of cancer emerged, mouse models have contributed to nearly every corner of cancer research, and these models have evolved well beyond simple transgenic or syngeneic models to a wider range of complex models, including CDX (cell line derived xenograft) and PDX (patient derived xenograft) mouse models and humanized mouse models.

But mouse models also have limitations that have been challenging and difficult to overcome. Mouse models are not people. There are genetic similarities, but they are not identical, and it is those differences that can impact drug discovery efforts and the overall translatability to the clinic.

While the majority of the mice Charles River sells are conventional mouse models, the demand for pricier humanized models—which are particularly coveted by mid-range biotech—are growing in tandem with the complexity of new advanced modalities.

To shed some light on the advantages and challenges of using conventional mice vs. humanized mice Eureka turned to two experts in our RMS business: Jenny Rowe, PhD, a Scientist III who provides technical and scientific oversight for humanized mouse model development and production at Charles River and Steven Bronson, DVM, a Scientific Product Manager who currently supports the immunodeficient rodent and humanized mouse portfolio. Based on their shared expertise, here are five points to consider when using these models.

When is it better to use a humanized model vs. a conventional model (such as the C57BL/6 mouse)?

First, we should discuss what we mean by the term humanized and conventional mice.

Conventional mouse models are immunocompetent mouse strains such as the C57BL/6. These types of mice can be used as a foundational research model in a series of studies or to provide preliminary information that influences future studies using humanized mouse models.

Immunodeficient mouse strains are important as they can be used for many types of studies and can host a wide range of tumor cells including CDX (cell line derived xenografts) and PDX (patient derived xenografts). They can also be humanized. Humanized models work best in severely immunodeficient mouse strains.

Humanized mice refer to a few different types of models, including mice that have been engrafted with human immune cells or tissues or mice that have had human genes inserted into their genome. It is important to distinguish if the work requires the presence of a human gene(s) or a partial human immune system. When we refer to humanized mice in this article, we are talking about humanization of the immune system, which can occur either through engraftment of hematopoietic stem cells or the engraftment of peripheral blood mononuclear cells.

Humanized models are implemented when evaluating questions related to immune responses to a therapeutic agent in a human disease setting. It is important for a researcher to be aware of the limitations of the models being used to optimize the experimental arm for their intended use.

What questions do researchers need to take into account when choosing a humanized model?

While humanized mice provide valuable information in a preclinical setting, it is important to recognize that these models offer a partially reconstituted human immune system and may not address every aspect of the interactions in a fully functional human immune system. Researchers need to consider the implications and avoid overstating conclusions. Consideration needs to be taken into account regarding the presence and functionality of different human immune cell subpopulations.

What do the markets look like for conventional and humanized models, and is technology making it easier and cheaper to use humanized models?

Every segment—from global large and mid-range companies to academic and government labs— uses conventional mice as well as humanized mice, though Charles River’s market for humanized mice is predominantly in the mid-range biotech sector. The majority of Charles River’s clients use humanized mice for oncology studies, particularly immuno-oncology, though there is an increase in the number of clients looking to use them for autoimmunity. And many clients are interested in learning more about the triple immunodeficient NCG mice.

In terms of technological advances, there are standard techniques and processes in creating humanized models that remain the gold standard for robust immune reconstitution (cord blood-derived human CD34+ cells). However, there are also areas with focused research into organoids or attempting to push differentiation of stem cells into particular lineages of interest that are gaining momentum. As technology continues to advance, it would be great to see humanized models with more complete and functional immune systems become available. To date, these costs remain quite high and are actually increasing every year, mainly because the cost of cells, mice, and maintenance keep rising.

Is there an argument to be had that humanized mice are really the best model across the board given the difficulties translating conventional animal data to humans?

There are pros and cons to all models. Humanized mice do help bridge the gap between traditional/conventional models and human trials by providing an opportunity to study human biological processes in vivo that would otherwise not be possible. However, there are basic scientific questions that a researcher may be asking that can be performed in a non-humanized mouse model (whether it be an immunodeficient or conventional mouse strain). These types of questions would not be linked to any direct interaction with a component of the human immune system.

Are there new areas of research/diseases for which humanized mouse models might be a good fit?

The humanized field is always looking for opportunities to enhance or build upon existing humanized models in order to better meet the scope of the research need.

Many of the next-generation humanized models stemmed from a need to evaluate a certain human cell population in an environment that more closely mimics what is observed in humans. Autoimmune disorders continue to be an area where more predictive models are needed. And orthotopic cancer models are employed more and more often to offer an improved view of the interaction of the tumor with the components of the human immune system that are present.

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