Humanized rats are specialized animal models engineered to incorporate human biological components. This allows scientists to study human diseases and biological processes within a living system that resembles human physiology. Their development bridges gaps between laboratory experiments and human clinical trials, aiding in understanding complex human biology and developing new medical interventions.
Understanding Humanized Rats
Humanized rat models involve introducing human elements into a rat’s biological system. This can include human genes, cells, tissues, or gut microbiota, creating models that mimic human physiological conditions or disease states more accurately than standard animal models. These modifications allow researchers to investigate human-specific biological interactions.
Different types of humanization serve unique research purposes. Some rats carry specific human genes, such as those involved in iron homeostasis, where the rat’s gene is replaced with its human counterpart. Other models are engineered with a human immune system by transplanting human immune cells or their precursors into immunocompromised rats. Humanized gut microbiota models are also created by introducing human fecal microbes into rats, often germ-free animals, to study the impact of human gut flora on health.
The Process of Creating Humanized Rats
Creating humanized rats involves sophisticated methods to integrate human biological components. Genetic engineering, including CRISPR-Cas9, is one common technique. This technology allows scientists to precisely edit the rat’s genome by inserting, deleting, or replacing rat genes with human ones. For example, CRISPR-Cas9 has replaced rat genes like Tfrc and Tf with human coding sequences, creating rats that express human transferrin receptor 1 and transferrin.
Cell transplantation is another widely used method, often performed by introducing human stem cells or immune cells into rats with suppressed immune systems. Severely immunodeficient rat strains, such as the Sprague-Dawley-Rag2tm2hera Il2rgtm1hera (SRG) rat, are frequently used as recipients because their lack of a functional immune system prevents rejection. Human hematopoietic stem cells (HSCs), which develop into various blood cell types, are often injected to reconstitute a human immune system within the rat. Researchers have also successfully engrafted full-thickness human fetal skin, along with autologous fetal lymphoid tissues and hematopoietic stem cells, to create humanized skin and immune system models.
Microbiota transplantation involves introducing human gut bacteria into rats to establish a human-like microbiome. This process typically uses germ-free rats, which are devoid of all microorganisms, to ensure successful colonization. In some cases, antibiotic pretreatment in conventional rats reduces native gut flora, making them more receptive to human microbial communities. This allows for the study of host-microbiota interactions in a human-relevant environment.
Their Role in Advancing Medical Science
Humanized rats are important tools in various fields of medical research. Their ability to mimic human physiology more closely allows for a deeper understanding of disease mechanisms and the testing of new therapies. These models are particularly useful where human-specific pathogens or responses are involved.
Infectious Disease Research
Humanized rat models benefit infectious disease research, particularly for pathogens that do not effectively infect or trigger appropriate immune responses in standard rodents. They enable the study of Methicillin-resistant Staphylococcus aureus (MRSA) infections in humanized skin models, which can accurately recapitulate clinical presentations. These models also enable researchers to investigate human immune responses to viral infections, including HIV and Hepatitis B, by providing a functional human immune system. Studying human-specific host-pathogen interactions in vivo accelerates the development of vaccines and antiviral treatments.
Cancer Biology
Cancer biology utilizes humanized rats for testing new therapies on human tumors grown within them. Immunodeficient strains like the SRG OncoRat® support human cancer cell lines and patient-derived xenografts (PDX), allowing assessment of tumor growth and response to anti-cancer drugs. These models are valuable for immuno-oncology studies, providing a platform to evaluate immunotherapies like checkpoint inhibitors. Rats’ larger size compared to mice allows for larger tumor volumes and serial blood sampling, providing more comprehensive drug efficacy data.
Immunology
Humanized rats contribute to immunology by providing a system to study human immune responses and the development of human immune cells. Models reconstituted with human hematopoietic stem cells can develop diverse human immune cell lineages, enabling researchers to investigate complex immune cell interactions and autoimmune diseases. They can also be used to understand graft-versus-host disease (GvHD) in human cell transplantation.
Drug Development and Neurological Disorders
In drug development, humanized rats help assess drug efficacy and toxicity in a human-relevant system. By incorporating human drug-metabolizing enzymes or transporters, these models can predict how human bodies process medications. This allows for more reliable preclinical testing, potentially reducing high failure rates of drug candidates in human clinical trials. Their use also extends to neurological disorders, where human brain cells or organoids can be transplanted into rat brains to study neurodevelopmental conditions like autism and epilepsy. These models allow for detailed observation of human neuron growth, connections, and responses to potential treatments.
Considerations for Their Use
The use of humanized rats in scientific research involves several important considerations. Ethical considerations regarding animal welfare are important, requiring strict adherence to guidelines that ensure humane treatment of these animals. Researchers must minimize discomfort or distress to the rats during their care and experimental procedures. The use of human biological material also introduces ethical discussions, requiring careful oversight and adherence to regulations.
Even with humanization, these models retain inherent limitations because they are still rats, not humans. While they offer improved relevance, they cannot fully replicate the entire complexity of human physiology, disease progression, or immune responses. The creation and maintenance of humanized rats are also complex processes, requiring specialized facilities, expertise, and resources. This complexity contributes to higher costs compared to standard rodent models, with the humanized mouse and rat model market valued at hundreds of millions of dollars globally. These factors influence their widespread accessibility and application in research settings.