Animals have been used in scientific research for centuries. Starting in the 20th century, the use of animal models for different pathologies became standardized and regulated. There are many different animal models used to investigate diseases including mice, rats, zebrafish, non-human primates, guinea pigs, fruit flies, and others. Different animal models are used to answer different scientific questions. Additionally, animals are used to demonstrate to the U.S. Food and Drug Administration (FDA) that drugs developed in the lab are not only effective, but safe for humans. As a result, scientists have made major scientific and therapeutic advances with the help of animal models.
Specifically, scientists began using mice because of their genetic similarity to humans. It is also easy to manipulate mouse genetics and inbreed mice to express the same genes and cellular traits. Quickly, institutions began using mice to isolate different cell pathways, genes, and organs to understand how the body worked and to develop therapies against disease. Today, mice are still a vital necessity for the advancement of basic scientific discoveries and therapeutic development.
A recent paper published in Science Immunology, by Dr. Enfu Hui and others, discovered that a cell marker known to inhibit the immune response in cancer is stronger in humans than mice. This discovery has major implications in how we develop therapies and study foundational biology. Hui is an Associate Professor in the Department of Cell and Developmental Biology at the University of California San Diego (UCSD). His work focuses on cell biomarkers that regulate the immune response in different pathologies such as cancer. Specifically, he investigates the function of these biomarkers and works to improve immunotherapies.
The cell marker Hui and others investigate is known as an immune checkpoint marker. These markers are expressed on cells and prevent immune cells from recognizing and eliminating infections. Specifically, programmed death-1 (PD-1) is expressed on immune cells and acts as a natural safeguard to avoid killing healthy cells. In healthy cells, this checkpoint will bind to its receptor on another cell telling the immune system to not eliminate it. However, tumors evolved to express the PD-1 receptor, which employs the safeguard mechanism to avoid immune cell activation. Most of our knowledge of this marker is due to mouse studies.
Hui and his team discovered the evolutionary roadmap of PD-1 and traced it back millions of years. As a result, they found that PD-1 expression is much weaker in mice compared to humans. Although mouse and human genetics are similar, they are not the same. This work uncovers specifies specific features of the immune system which can lead to improved preclinical models for developing therapies. The team compared mouse PD-1 with human PD-1 and found that the two do not have all the same amino acids that make up the protein. Further analysis demonstrates that an ancestral rodent millions of years ago that had similar PD-1 to humans became extinct and is thought to have been attributed to adaptational pressures. These discoveries imply that scientists need to have a rigorous understanding of the models they are working with to translate therapies to the clinic. Overall, Hui and others have provided key information that will transform how we study disease and develop successful cancer treatment.