Treatment for Fatal Prion Diseases: The Promise of CHARMs in Gene Silencing

Prions diseases occur when a protein regularly found in the body is misfolded, causing illness. This misfolding leads to brain damage alongside other symptoms, which take years to develop. Once a person is symptomatic, the disease rapidly progresses in the body, leading to death. Researchers at the Broad Institute of MIT and Harvard and researchers from the Whitehead Institute for Biomedical Research have developed promising new therapies for fatal prion diseases. The collaboration between the two programs led to the development of a new set of molecular tools known as CHARMs (Coupled Histone tail for Autoinhibition Release of Methyltransferase), which silences the gene that causes the production of the disease-causing proteins, alongside stopping the production of more of these genes, CHARMs can also stop already generated prion protein genes. One of the researchers, Sonia Vallabh, pushes the urgency of this project as she suffers from an increased likelihood of developing fatal familial insomnia, another form of prion disease. While initially starting in the law industry, Vallabh and her husband shifted their careers toward biomedical research after discovering a lack of treatments for these conditions. Their work doesn't only focus on treating prion disease, but they continue to research other disorders that cause the loss of neurons in the brain caused by toxic protein accumulation.


The CHARMs technology uses epigenetic editing, which uses an epigenome, a make-up of chemical compounds and proteins that can attach to DNA and allow actions such as turning genes on or off, which specifically targets the prion protein gene, quickly silencing them and preventing any more production of misfolded proteins which may have led to a prions diseases. Tests conducted on mice confirm that these tools can remove up to 80% of prion proteins found in the brain, a significant increase from the 21% removal rate used with past techniques to relieve symptoms. The researchers saw challenges when creating CHARMs, especially in trying to ensure that the components used were non-toxic, alongside being able to target the prion gene without any side effects. Using the machinery built into the cells, the researchers could silence the gene, minimizing the potential toxicity. While the development of CHARMs is still too unsafe for humans, the astonishing rate of development shows hope for those who suffer from prion diseases and other diseases caused by protein misfolding.


While new tools to treat prion diseases are being developed at astonishing rates, it will still be a while before CHARMs can be used to treat humans with prion disease. When the time comes when CHARMs are safe to use, they will revolutionize the medical field, helping prevent the decline in mental capacity due to misfolding. I find this article very reliving as while prion disease doesn't run in my family, Alzheimer's does, and both are similar to where misfolding can lead to a decline in cognitive functions. While not the same, if the development goes well for CHARMs to help treat prion disease, it could be used as a stepping stone to preventing Alzheimer's as well.


https://news.mit.edu/2024/charmed-collaboration-creates-therapy-candidate-fatal-prion-diseases-0627

https://www.usatoday.com/story/news/health/2024/06/27/stop-dementia-delay-brain-disease-medical-research/74190613007/

The Epigenetic Impact of Obesity: Do Fat Cells Have Memories?

 

A recent study looking into the fat cells of mice and humans has rewritten our current understanding of weight-loss on a molecular level. In fact, the commonly known "yo-yo effect", the inability to lose weight without it coming back, may finally be explained. 

To begin, epigenetics refers to how the environment and our behaviors may influence gene activity. Researchers at ETH Zurich analyzed the fat cells of overweight mice who had recently lost weight, and quickly noticed that obesity leads to distinct epigenetic changes in the nucleus of these cells, even after losing the weight. When eating the same diet, the once overweight mice gained weight at a faster rate than mice who had never been obese. This memory mechanism was also found in the fat tissue of humans, who had undergone weight-loss surgeries. 

At this time, it is not possible to medically erase the epigenetic memory of fat cells or to tell how long these cells remember obesity in general; however, we do know that fat cells live for about ten years. To mitigate against the "yo-yo" effect, it is recommended to be mindful of your health and avoid obesity to begin with. 

This research is intriguing to me because I am interested in going into the field of pharmaceutical research; therefore, I am eager to see if a new breakthrough of medication to combat the memory of these fat cells is possible. I also found it fascinating that almost all other cells in our body have been found to have memories. As someone who enjoys fitness in my personal life, I have always heard the term "muscle mass" thrown around and have wondered if it had any scientific basis, which it does!

https://www.sciencedaily.com/releases/2024/11/241118125210.htm

https://www.nature.com/articles/s41586-024-08165-7

Active Genetics the New form of inheritance

Active Genetics the New form of inheritance

In 2015, Researchers at University of California San Diego developed a breakthrough technique called active genetics. Active genetics allows parents to transmit most of a genetic trait to their offspring instead of the 50% of trait that would be transmitted in nature genetic inheritance. In an experiment using CRISPR/Cas9 to edit regulatory elements in native genomic environments, researchers found that active genetics are efficient in target gene insertion. Target gene insertion is also called transgenesis which is a single step replacement of genetic control elements. The study followed the genetic control of a gene responsible for coordinating the formation of a wing vein in fruit flies. The goal was to understand how the genetic mechanism that controlled the expression of this gene in time and space, then to hypothesize how this gene circuit evolved in the other species. From this study the researchers understood that interactions between chromosomes contribute to the control of gene activity. These interactive points could be potential target for epigenetic intervention. The study also demonstrated that general utility of active genetics as a form of engineering new organisms with novel traits. For active genetics to be used transgenesis, researchers have created a “CopyCat” cloning vector. This vector can be inserted into the genome at any desired location and get copied with high proficiency from one parental chromosome to another so that the offspring receive the CopyCat gene. This technique has the potential to develop solutions and advancements in multiple fields ranging from health to agriculture. I found this article to be extremely interesting because it proposes a direct route to manipulate the genome. This could improve gene therapies. The use of active genetics in transgenics seems similar to the concept of cloning a gene with plasmids. If this technique advances scientist might be able to replace a defected gene in a parent with a properly working gene so that the child will have a smaller risk of inheriting that defected gene.

Cuddling Affects Gene Expression

There has been a study by the University of British Columbia in Canada that when a baby is not cuddled or given much physical touch their gene expression can be affected.  This is a very new study, so it still is not clear what exactly is causing the gene expression to change.  During the study, the parents were asked to keep track of their cuddling with their babies and after four and a half years later their DNA was sampled.  In the samples, the children who had low contact had differences in DNA methylation at five different sites.  There was also a difference in epigenetic ageing that was different from their actual age.  There needs to be more studies done to actual identify what exactly about not receiving  physical touch causes genetic expression changes. 

https://www.sciencealert.com/cuddling-babies-alters-genetics-dna-for-years

The Famine Ended 70 Years Ago, but Dutch Genes Still Bear Scars

The Dutch Hunger Winter has proved unique in unexpected ways. Because it started and ended so abruptly, it has served as an unplanned experiment in human health. Pregnant women, it turns out, were uniquely vulnerable, and the children they gave birth to have been influenced by famine throughout their lives. When they became adults, they ended up a few pounds heavier than average. In middle age, they had higher levels of triglycerides and LDL cholesterol. They also experienced higher rates of such conditions as obesity, diabetes and schizophrenia.

“How on earth can your body remember the environment it was exposed to in the womb — and remember that decades later?” wondered Bas Heijmans, a geneticist at Leiden University Medical Center in the Netherlands. Well, at millions of spots across our DNA, genes may carry a methyl group, which seems to silence genes and disrupt how normal cells use genes. Researchers found a few methyl groups that were linked both to the famine and to health conditions later in life. Their study suggests that the Dutch Hunger Winter silenced certain genes in unborn children — and that they’ve stayed quiet ever since. In the future,with carefully controlled experiments, researchers can shed more light on how a pregnant mother’s food supply affects the epigenetics of her offspring.


https://www.nytimes.com/2018/01/31/science/dutch-famine-genes.html 
http://advances.sciencemag.org/content/4/1/eaao4364