CRISPR in animals (Part 50- CRISPR in gene editing and beyond)
Welcome to the 50th part of the multi-part series on applications of CRISPR in gene editing and beyond.
CRISPR has various applications for animals as well.
Models for human diseases
CRISPR gene editing technology has been used in various animals to generate disease models that can help researchers better understand and develop treatments for human diseases (Shrock and Güell, 2017; Zarei et al., 2019; Khalaf et al., 2020).
Mouse models are one of the most widely used animal models for studying human diseases using CRISPR gene editing. This is because mice share many genetic and physiological similarities with humans. This involves modifying their genomes to mimic the genetic mutations or variations that are associated with specific human diseases. These animal models can then be used to study the underlying mechanisms of the diseases, test potential treatments, and identify new targets for drug development (Birling et al. 2017; Lu et al., 2019; Sharma et al., 2021; Lim et al., 2022).
For example, researchers have used CRISPR to create mouse models of cystic fibrosis, a genetic disorder that affects the lungs and other organs. By introducing mutations in the mouse genome that mimic the human genetic mutations that cause cystic fibrosis, researchers were able to create mice that develop lung diseases similar to that seen in human patients. These mice can then be used to test potential therapies and identify new drug targets for cystic fibrosis. Mouse models have been used to study a wide range of human diseases, including but not limited to Huntington’s disease, sickle cell disease, muscular dystrophy, retinitis pigmentosa, cancer, diabetes, and various other genetic diseases. The mouse models provide valuable tools for studying disease mechanisms and testing potential therapies.
While mouse and rat models are commonly used for studying a wide range of human diseases, larger animals such as pigs and monkeys may be preferred for certain disease models due to their physiological and anatomical similarities to humans. One example is the study of cardiovascular diseases such as heart disease and stroke. Pigs have a cardiovascular system that is more similar to humans than mice, making them better models for studying these diseases (Perleberg et al., 2018; Hou et al., 2022). Furthermore, pigs have the advantages of early sexual maturity, a short reproductive cycle, and a high number of offspring per litter. One study used CRISPR gene editing to create pigs with a mutation associated with human familial hypercholesterolemia, a condition that causes high cholesterol levels and an increased risk of heart disease (Yao et al., 2016; Huang et al., 2017; Zhao et al., 2019). The pig models were able to replicate key features of the disease, making them useful for studying its underlying mechanisms and testing potential treatments.
Another example is the study of neurological disorders such as Parkinson’s disease and Alzheimer’s disease. Monkeys are more similar to humans in terms of brain structure and function, making them better models for studying these diseases. Researchers have also used macaques as a model for studying autism spectrum disorders (ASDs) because they share many similarities with humans in terms of brain structure, social behavior, and communication (Park et al., 2019; Aida and Feng, 2020). For example, researchers used CRISPR/Cas9 to delete the SHANK3 gene associated with autism in fertilized macaque eggs, which were then implanted into surrogate mothers. The resulting offspring showed several behavioral and neurological abnormalities that were similar to those seen in humans with ASDs, such as reduced social interaction and repetitive behaviors (Zhao et al., 2018; Tu et al., 2019).
In general, larger animal models such as pigs and monkeys can provide a more realistic and clinically relevant model for certain human diseases than mouse and rat models. However, they also come with additional ethical and logistical considerations, such as higher costs, longer gestation periods, and greater regulatory oversight. Therefore, the choice of animal model ultimately depends on the specific disease being studied and the scientific questions being addressed. But with all animal research, it is important to ensure that the animals are treated humanely and that their use is justified by the potential benefits to human health.
Overall, the use of CRISPR to create animal models of human diseases is a promising area of research that has the potential to greatly advance our understanding and treatment of a wide range of diseases. By creating animal models of human diseases using CRISPR, researchers can gain valuable insights into the underlying mechanisms of these diseases, and test potential treatments in a controlled and ethical manner. These animal models also provide a valuable tool for drug development and testing, as they can help to identify new drug targets and test the safety and efficacy of potential therapies before they are tested in human patients.
Xenotransplantation
CRISPR has the potential to revolutionize the field of organ creation and transplantation. There are currently many challenges associated with organ transplantation, including a shortage of donor organs and the risk of rejection by the recipient’s immune system. CRISPR offers a hopeful solution to these challenges by enabling the creation of organs that are more compatible with human recipients.
One of the most promising applications of CRISPR in organ creation is Xenotransplantation, i.e., the transplantation of organs from one species to another. CRISPR has the ability to edit the genomes of other species to make their organs more compatible with human recipients (Ryczek et al., 2021). Pigs are a particularly optimistic source of organs for xenotransplantation because their organs are anatomically and physiologically similar to human organs. However, pig organs contain antigens that can trigger an immune response in humans called as hyperacute rejection (HAR) process, which can occur within minutes to hours after transplantation. HAR is a type of rejection that is mediated by antibodies naturally present in the human recipient, which bind to specific epitopes on the porcine endothelial cells. This binding triggers the activation of the complement system, leading to the destruction of the graft’s vascular system and subsequent transplant failure. This immune response is characterized by damage to the vessels, swelling, bleeding, and clotting.
The main xenoantigen involved in HAR is the galactose-α1,3-galactose (α-Gal) epitope, which is produced by the porcine GGTA1 gene. This enzyme is found in pigs, but not in humans, and triggers the production of antibodies in humans. Additional antigens like, Neu5Gc and β4GALNT2 also significantly influence HAR. With CRISPR, it may be possible to edit the pig genome to inactivate these porcine genes. This could make pig organs suitable for transplantation in humans without triggering an immune response that leads to transplant failure (Zhang et al., 2018; Cowan et al., 2019; Wang et al., 2019).
Another challenge of pig organ xenotransplantation is the risk of infection with porcine endogenous retroviruses (PERVs), which are present in the DNA of all pigs. While PERVs are not harmful to pigs, there is a possibility that they could infect human recipient cells, potentially leading to disease. Scientists are working to develop methods to eliminate PERVs from pig cells using CRISPR before transplantation (Niu et al., 2017; Ross and Coates, 2018).
In addition to pig-to-human transplantation, CRISPR can also be used to create organs from scratch by editing the genomes of stem cells. For example, scientists have used CRISPR to edit the genomes of stem cells to differentiate them into functional liver cells, which could eventually be used to create a liver for transplantation.
While there is still much research to be done in this area, CRISPR has the potential to overcome many of the barriers that have made organ transplantation difficult in the past, improving the lives of countless individuals around the world. However, it is important to proceed with caution and ensure that any use of CRISPR in organ creation is safe, ethical, and well-regulated.
For livestock
CRISPR has several applications in livestock, including improving animal health, productivity, and disease resistance (Jabbar et al., 2021; Singh and Ali , 2021; Yunes et al., 2021; Mehra et al., 2022). One of the main uses of CRISPR in livestock is to create animals that are resistant to diseases, such as African Swine Fever or Foot-and-Mouth disease. For example, researchers could edit the genes of pigs to delete or modify a receptor that allows the African Swine Fever virus to enter their cells, making them resistant to the disease. Similarly, scientists could edit the genes of cattle to make them more resistant to Foot-and-Mouth disease.
Another application of CRISPR in livestock is to improve animal productivity. For example, CRISPR can be used to modify genes that regulate the cow’s mammary gland development, resulting in increased milk production. CRISPR can also be used to modify genes that regulate the composition of the milk, resulting in milk with higher protein or fat content and reduced levels of allergens or lactose. These modifications could have important benefits for dairy farmers, who could improve the efficiency of their operations and increase their profits by producing more milk of higher quality. Additionally, by producing milk with specific properties, farmers could meet the growing demand for specialized dairy products, such as high-protein or lactose-free milk.
Similarly, researchers can use CRISPR to modify genes (e.g., Myostatin gene) that regulate the animal’s muscle development, resulting in leaner meat.
However, the use of CRISPR in livestock also raises ethical concerns. Some argue that it is unethical to genetically modify animals for human benefit, particularly if it causes suffering or reduces their quality of life. Additionally, there are concerns about the potential impact on the environment and natural ecosystems if genetically modified animals escape into the wild.
There are also concerns about the long-term effects of genetic modification on animal health and the potential for unintended consequences. It is possible that editing the genes of livestock could have unforeseen effects on their physiology or behavior, potentially leading to negative impacts on their health and well-being. For example, creating animals with increased productivity could lead to health problems or reduced lifespans. Mutations in the myostatin gene have also been associated with muscle disorders in some species.
It is therefore important to carefully evaluate the potential risks and benefits of using CRISPR to modify the genes in livestock and to ensure that any research or applications are conducted in an ethical and responsible manner. Additionally, regulatory frameworks must be in place to ensure that genetically modified livestock and their products are safe for human consumption and do not pose any environmental risks.
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