The 30 Year Wait for a Nobel Prize: MicroRNA

 

In 1993, two scientists, Victor Ambrose (professor of natural science at UMass Chan) and Gary Ruvkun (genetics professor at Harvard), made a discover that completely rewrites our understanding of gene regulation and genetics as a whole. Unfortunately, this discovery was met with "deafening silence from the scientific community" (Nobel Committee). Finally this year, the two were granted with a long-overdue Nobel Prize of Physiology or Medicine for their discovery of microRNA, and its role in post-transcriptional gene regulation. 

To further explain, the two began researching C. elegans (1-millimeter-long roundworm) in the late 1980s as postdoctoral fellows at MIT. After separating, they both continued to research the roundworm and Ambros made an interesting discovery. While looking into a mutation, he noticed a small fragment of RNA (microRNA) blocking the lin-14 gene by binding to mRNA. Before this discovery, it was believed that gene regulation was controlled only by transcription factors, which would give cells specialized purposes. Thus, skin cells would function as skin cells and not brain cells, as an example. Even facing criticism that this was unique to simpler organisms like the C. elegans, the two published this finding in 1993 and furthered their research into the animal kingdom. 

In 2000, the two found that the same mechanism of microRNA plays a titular role in gene regulation in many species in animals as well. Since then, they have identified over 1,000 different genes for microRNA in humans. Additionally, each microRNA regulates many different types of genes, as well as genes being regulated by many types of microRNA.  

These findings are nothing short of incredible and it is amazing that Ambrose and Ruvkun are getting the recognition for this discovery in such a big way. I am excited to see what will come next for the two, and it is always very intriguing to see the "laws" of genetics being rewritten even today. 

https://www.usnews.com/news/health-news/articles/2024-10-07/u-s-scientists-win-nobel-prize-in-medicine-for-discovery-of-mrna

Arsenic resistance in roundworms and bacteria

Recently, researchers have been looking into arsenic toxicity in roundworms and bacteria. Arsenic trioxide is a compound that has been used as effective treatment of some cancers, including acute promyelocytic leukemia. Despite its success, some patients will experience side effects that are a result of arsenic toxicity.

In order to understand these processes more, researchers looked into strains of bacteria (Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Staphylococcus aureus) and various wild type species of roundworms. They wanted to find out more about the process of how these organisms are able to tolerate various levels of arsenic trioxide toxicity and how this information could be translated to humans to possibly determine whether or not some people will have a reaction to chemotherapy using arsenic trioxide.

In the various strains of bacteria, the main thing researchers found was that there were three genes that contributed to their arsenic resistance: arsA, arsB, and arsC. Although all three genes code for completely different proteins, the researchers found that all three are needed for the bacteria to express arsenic resistance. There was also a new gene that was discovered in the bacteria, named arsD, which sets an upper limit for the expression of arsA, arsB, and arsC, suggesting that there is a possibility that a high enough dose of arsenic trioxide could still be lethal to bacterial strains with these genes.

In the second paper, researchers decided to study roundworms because of the similarity of their cellular processes to humans. The effects they studied included mitochondrial toxicity, generation of reactive oxygen species, genotoxicity, genome-wide shifts in chromatin structure, reduced lifespan, and induction of a heat-shock response. One of the biggest findings of the paper was the fact that variation in the dbt-1 gene is what causes variation in arsenic trioxide response. The paper also proved that only a single missense variant is needed in the dbt-1 gene to vary the response to arsenic for roundworms. The single missense causes a cysteine to be changed to a serine which causes irreversible changes down the line, reducing the arsenic resistance in the roundworms. As a part of the experiment, the researchers also used CRISPR/Cas-9 genome editing to see if they could revert the roundworms back to their normal state (reverse the missense). This experiment was successful, suggesting that in some cases arsenic trioxide resistance can be altered by altering ones genome.

Overall, I think these studies are really interesting since not many people think about studying roundworms to further cancer studies. Even though some chemotherapies are successful in treating aggressive cancers, they may not always be the best option for the patients. If researchers are able to find pathways coded by genes, it may be possible to test patients and determine their risk of side effects before they begin chemotherapy. Finding specific pathways may also lead to new treatment discoveries. In people who may be exposed to different levels of arsenic trioxide, knowing the molecular pathways may also allow doctors to treat arsenic poisoning more effectively. Using simple model organisms like bacteria and roundworms to be able to make comparisons allow for new doors to be opened for treatments in humans.

Links to the papers:

Orphan enzyme or patriarch of a new tribe: the arsenic resistance ATPase of bacterial plasmids
https://onlinelibrary.wiley.com/doi/epdf/10.1111/j.1365-2958.1993.tb01607.x

Natural variation in arsenic toxicity is explained by differences in branched chain amino acid catabolism
https://doi.org/10.7554/eLife.40260.001

Hermaphroditic roundworms lose half their genome from sister species when self fertilizing

An article done by the New York Times describes how tiny roundworms, Caenorhabditis briggsae and Caenorhabditis nigoni are extremely similar genetically, but very different in their sexual reproduction processes. In order for C. nigoni to mate, there needs to be a male and a female for fertilization to take place. This is different for C. briggsae however, in that they are able to self-fertilize by producing sperm to fertilize their own eggs. Because C. briggsae are hermaphroditic, there is no need for sexual reproduction. This genetic adaptation has occurred because there is a lack of males in the population. In a study published in Science in the beginning of January of 2018, biologists found that since the hermaphroditism took place in the one set of roundworms, it lost half of the genes since it broke away from C. nigoni approximately a million years ago. A study done by the University of Maryland-College Park concludes that this loss of genes is related to the male population which is dwindling in numbers. When introduced to the male secreted short genes (m.s.s.), C. briggsae produced more offspring than the hermaphroditic organisms. Dr. Haag from the University of Maryland-College Park suggests that these organisms leaning towards hermaphroditic lifestyles may “put a break on population”.


This article I found very interesting. It’s neat to see how hermaphroditic traits in one roundworm compared to their ancestral sister alter their entire genome. Although the roundworm C. briggsae do not yield as many offspring through self-fertilization unlike if they were to be in contact with a male, it provides evolutionary traits in that population growth and size can be halted/reduced. It’s also hard for these worms to find mates as well, which make it hard for new colonies of C. briggsae to get started.

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