This week we learned more about techniques used in molecular and cellular neuroscience from Ohio Wesleyan University professor, Dr. Suren Ambegaokar. While Cellular Neuroscience focuses on the inner workings of a single cell or the system level integration of multiple cells, Molecular Neuroscience looks at the function of individual components of the cells, like genes and proteins. Dr. Ambegaokar’s work is more closely aligned with Molecular Neuroscience.
One technique used in this field is the transgenic model, which is an animal model where new genetic information is injected into the embryo and then researchers can see what functions of the animal have changed. Dr. Ambegaokar gave the class an example of fruit flies being genetically malleable and used in studies often. The fruit fly’s eyes are mostly neural tissue making it an external neuron. In this example the fruit fly is used to study the effect of a gene found to be part of causing Alzheimer’s disease in humans. Dr. Ambegaokar explained autophagy related to these studies. Autophagy is the process that targets things that are having harmful effects. In the case of Alzheimer’s disease, it has been discovered through a variety of studies that this process of autophagy is disrupted.
Transgenic animal models are used to study a variety of neurodegenerative diseases and their effects. ShihuaLia reviews the use of several transgenic models, for example transgenic mice. The transgenic mice are known to show very similar neuropathology and phenotypes expressed in their respective diseases. In this article it expresses how these animal models are used to look at the neurodegenerative effects of Huntington’s disease. There are differences between the larger or smaller animals used. Larger animals could experience a toxic effect from a specific change in their proteins whereas the smaller animals, such as mice, might not. On the other hand, some neuropathologies are more easily uncovered in larger animals than they are in smaller ones. Transgenic animal models are a vital aspect of molecular and cellular neuroscience; they help continue to help us understand the cellular and molecular pathways of diseases and reveal potential treatments.
Dr. Ambegaokar discussed how interaction between different eye pigment genes and tau induced neurodegeneration in drosophila melanogaster. Dr. Ambegaokar’s studies have demonstrated how white, brown, and rosy genes dose dependently affected the tau-induced eye phenotype, tau phosphorylation, and GSK-3b activity. They also explored how the w1118 homozygotes showed a significant reduction in eye size increased ommatidial disorganization as compared to w+/w1118 heterozygous flies. He described his studies on white and brown, and how the loss of function mutations in these colors induce tau-induced toxicity. As he got deeper into his studies, he discovered that granules with improper pigment balance due to white, brown, or scarlet mutations become autolysosomes. This in turn caused lysosomal dysregulation, which is a characteristic feature of Niemann–Pick disease type C and Sanfillipo syndrome type B, both tauopathies. In conclusion, this shows that studies on how fruit fly genetics affect neurodegeneration can be used in similar instances in human cases.
Based on our discussion with Dr. Ambegaokar, we wondered how this kind of research might be applicable to COVID-19; how can we use fruit flies to study human diseases, especially COVID-19? Although it might seem peculiar at first, Wong et al. and Chan et al. have used fruit flies to study how SARS-CoV-1 from the 2003 outbreak causes cell death. Researchers have even studied HIV Tat protein using fruit fly models, and their findings have been observed in mammalian cells as well, thereby demonstrating that transgenic models as simple as fruit flies can be successfully used to study viral gene expression. Dr. Ambegaokar, too, believes that it is possible to make transgenic models that express human proteins targeted by Sars-CoV-2, such as the ACE2 receptor protein. “There are some people trying to work on animal models for COVID, and the way they’re doing that is by trying to express the human ACE2 receptor in mice or other animals.” Mice have a slightly different version of ACE2 that is enough to make them less susceptible to SARS-CoV-2. “By copying the human gene into a mouse you’re more likely to be able to get a mouse to be actually infected with the virus.”
However, Dr. Ambegaokar points out that “you always have to control where it is going to be expressed and what tissue it is going to be expressed.” It is important to limit the gene expression to a specific tissue, such as the lungs, the gut, or the blood vessels of the mice. “It is hard to get it to be expressed in exactly the same pattern as it would be in humans. So, most of our genetic regulation control is to either express it in one tissue or express it in everything.”
Transgenic models are excellent for studying molecular pathways, but the knowledge gleaned from them cannot always be quickly translated into treatment for humans. This, unfortunately, is the case for Dr. Ambegaokar’s research on Alziehemer’s. “Even though we know or we feel pretty confident that this is what’s happening in the brains, it’s unclear how you would treat it in a way that would be safe and helpful.” If something goes wrong, it might cause damage to healthy cells or trigger unwanted immune response. “When you’re talking about COVID in the brain, inflammation is a massive risk.” Since these factors need to be taken into account, it often takes a long time to make drugs and vaccines.
Nevertheless, can transgenic models potentially help us design methods to treat damage done by COVID-19 infection or even create vaccines? The answer is yes. Transgenic COVID models can help us identify which molecules or pathways are affected by the virus, which can be potential targets for drugs or vaccines. This is where another technique used in molecular and cellular biology can help us answer this question. Dr. Ambegaokar explains that it is possible to make antibodies that identify only the virus protein or a molecule altered by the virus while ignoring other healthy forms of the protein. This allows our immune system to find the viral protein or the impaired molecule and clear it. “[In the case of Alzheimer’s] It has worked well in animal models and it has been tested a few times clinically in patients but so far, thankfully, it hasn’t caused anything worse.”
How does this apply to treating the effects of COVID on the brain? According to Dr. Ambegaokar, these methods can potentially help in treating the disease, but they cannot recover the neurons that have already been damaged. “We have very little knowledge or idea of how to restore neurons to health”, and so it is important to look into the prevention of the disease. Stem cells are another possibility for future research in molecular and cellular biology that can help us study ways to prevent neural damage. For now, it is important to prevent the spread of the disease by means already available to us.