BIOB34 PODCAST #2

In recent studies, it has been found that non-human primates, specifically rhesus and synomolgus monkeys, are good models for gene editing research due to their similarity to humans. However, there are limitations in the current transgenic methods used, such as retroviral and lentroviral methods. More effective and precise transgenic methods are needed. There is also a need to accelerate the sexual maturation cycle of monkeys for research purposes. Mice are also used for genetic editing, but non-human primates are the best models for studying pathogenesis and neurological diseases. The most effective gene editing technologies used so far include CRISPR-Cas9 and TALEN. Awareness of gene editing and the use of non-human primates is important for funding and advancements in treatments and disease mechanisms. Hello and welcome back to Science Kids. This week we are going to be learning about recent developments on gene editing. Today we have our special guest with us, Shijita Tandren. She is here to discuss gene editing specifically in monkeys. Hey, thank you for having me. My pleasure Shijita. Can you explain a little bit about what you found in recent studies about gene editing and what you think about genetically modified monkeys for research purposes? Well, for some time now we have come to understand non-human primates have been one of the best models for researchers to look at. Statistically it has been proven that there is a 93% homologous genome between monkeys and humans, meaning they are very similar to humans in terms of evolution, physiology, immunology, pyrochemistry and even pathology. Specifically, rhesus and synomolgus monkeys are used for gene editing. However, the issue we are facing currently is the certain factors that limit researchers from using these genetically modified non-human primate models. Okay, so what are some of the limitations or are there any limitations at all? So yes, there actually are limitations that have to do with the development of the non-human primate models. Some of the traditional transgenic methods are inefficient, such as retroviral methods. They tend to be less precise and uncertain, which makes it harder to obtain genetically modified non-human primate models. There is also lentroviral method, however the issue with the gene modification site is that the fragments inserted into the non-human primate models can be no longer than 10 kilobytes, which again limits research. So what you are saying is we need more effective and precise transgenic methods? Yes, exactly. A possible solution could be combining gene editing technology with nuclear transfer and other technologies, which could help develop disease models more efficiently. Also another issue researchers ran into was the sexual maturation cycle of rhesus and synomolgus monkeys. The cycle is about 4-5 years, which is pretty long, and an accelerated reproduction would help the use of these non-human primates. Wow. Were they able to find a solution for this at all? Yes. A group developed testes xenotransplantation to accelerate spermatogenesis, meaning by removing and moving testes tissue blocks of a young synomolgus monkey to an adult mice, the spermatogenesis of the monkey was shortened to 24 months, and the obtained sperm was used for embryo development and transplantation to obtain healthy offspring of the synomolgus monkeys. So more development in methods to accelerate the reproduction cycle of non-human primates would further help this research in the making of genetically modified non-human primates. Interesting. And if the issue is genetically modifying monkeys, are there any other animals like horses that can be used for genetic editing that can provide better results for some of these methods, or are monkeys the primary usage? Well, yes. There are mice, which are actually often used for clinical research, and there have been successful studies where we were able to use gene therapy to treat diseases such as labor congenital amorphosis. However, non-human primates are the best models in terms of similarity to humans, and in studying pathogenesis, specifically neurological diseases. That makes sense. Okay, so going back to gene editing methods, what are the most effective gene editing technologies researchers have used to date? Well, there's CRISPR-Cas9, which has been proven to be effective. There was actually a study back in 2014 where researchers were able to obtain twin synomolgus monkeys carrying targeted mutation genes, and they were able to simultaneously knock out both genes. They also found that the mutation appeared in germ cells, which meant that genetic mutations treated by CRISPR technology can enable germline transmission. This led to other similar studies where CRISPR technology was used to take out other genes in adult synomolgus monkeys, and has become an effective gene editing approach. I also would like to mention that off-target effects have not been found in non-human primate models built by CRISPR-Cas9, but this could be due to the limitations of the number of detection sites, so it's hard to know if these monkeys did not have off-target mutations. So yes, off-target effects is an unavoidable factor that kind of limits the in-depth study of gene editing monkeys. There's also TALEN technology that has allowed successful gene editing in which a group of researchers were able to generate a gene in a mutated female synomolgus monkey with Rett syndrome. This is very significant because RTT synomolgus monkeys have many similarities to RTT patients in terms of genotype and phenotype. So this is a great breakthrough in clinical research. Wow, that's fascinating. And may I ask why you think it's important for us to be aware of gene editing and the use of non-human primates? Well, I believe it is important to bring awareness not only because exposure about gene therapy and its various methods and technologies brings funding for the development of these new technologies, but also because new developments occur every day and it leads to breakthroughs about treatments and for diseases and it will help scientists deeply study disease mechanisms in the future. I completely agree with you. This was very insightful and made me understand why research and genetic editing is a topic we should all be knowledgeable about. Thank you, Shijita, for sharing what you found with us today.