Finding Fruit in Flies: Therapy for rare diseases #MetabolismMondays

All the world’s a metabolic dance, early career scientists are leading the way!

Emerging perspectives in metabolism

This week we’ll meet Dr. Holly Thorpe, newly minted PhD from the Chow lab at the University of Utah, who is now continuing her research there as a postdoctoral fellow. Holly’s path into rare disease research began as an undergraduate when she studied multiple sclerosis through computational genetics. A paper from the Chow lab showing how a simple sugar rescued a rare metabolic disorder in flies sparked her fascination towards studying metabolism and rare diseases. Now a freshly minted PhD continuing as a postdoc, Holly models rare disorders like Phosphatidylinositol glycan biosynthesis class A congenital disorder in Drosophila, using the power of fly genetics to uncover disease mechanisms and therapeutic targets. The Chow lab specializes in precision medicine for rare diseases, using advanced genetic tools – demonstrating how basic science is actively curing diseases and impacting human health. Driven by curiosity and compassion, Holly’s research shows how foundational discoveries can become lifelines for patients with no other options. Check out more work from the Chow lab here!

What was your first introduction to the field of metabolism – what’s your first memory? Could you share your journey into studying metabolism using Drosophila and what inspired you to specialize in the field of rare diseases?

For my undergraduate research, I worked in a lab that used computational genetics to study Multiple Sclerosis. I knew from this experience that I wanted to work in a human disease genetics lab for graduate school, but I wanted to have a mix of dry and wet lab in my research. When I found the Chow lab, they had recently published a paper showing that supplementation of N-acetyl glucosamine rescued a Drosophila model of another rare glycosylation disorder. The idea that something as simple as adding a specific sugar to the diet could have an effect was so exciting to me. I knew I wanted to study rare metabolic disorders.

Walk us through the process of studying rare diseases and creating personalized therapies.

Many of the patients reach out to Dr. Chow for help. The rare disease world is interesting because oftentimes the parents of these patients have found each other and started their own communities and foundations. We have had multiple different foundations reach out to Dr. Chow about the running screens for their gene of interest. To screen for phenotypes, we typically start with an RNAi model and knock down the gene ubiquitously and in multiple different tissues in the fly such as the eye, neurons, and muscle cells. Then we look for any phenotypes that might arise. We have successfully used the Drosophila Genetic Reference Panel (DGRP), a group of wild-derived, inbred, fully sequenced flies, to look at the effects of natural genetic variation on the phenotypes. From that we are able to run statistical analyses, such as a genome wide association study (GWAS) to identify potential candidate modifiers.

Tell us how Drosophila serves as an extremely advantageous model for conducting studies on rare genetic disorders.

I think Drosophila are such a good model organism. Roughly 70% of human disease genes have a human orthologue, so we are able to study a lot of different disorders. Most of the disorders we focus on have neuronal phenotypes, and we are able to take advantage of the ability to mimic these phenotypes such as neuromuscular issues and seizures.

Tell us about Phosphatidylinositol glycan biosynthesis class A congenital disorder of glycosylation (PIGA-CDG). How did you work towards characterizing and establishing Drosophila model of PIGA-CDG and how do you think it will be a help in understanding of the pathogenesis of this understudied rare disorder?

PIGA-CDG is an ultra-rare neurodevelopmental disorder. It is caused by loss of function mutations in the gene PIGA which encodes a necessary protein in the glycosylphosphatidylinositol (GPI) anchor synthesis pathway. Patients typically present with seizures, hypotonia, and neurodevelopmental delay. In developing a PIGA model, we found that ubiquitous loss of PIGA in Drosophila was lethal, so we decided to look at more cell-type specific loss. Because of the neurological phenotypes seen in patients, a previous graduate student in the lab performed neuronal- and glial–specific knockdown of PIGA and identified a climbing and seizure defect, respectively. We also had a heterozygous knockout model created to see if ~50% loss of PIGA would give any phenotypes since homozygous knockout flies are lethal. We again found a seizure phenotype. Using these models, and other cell specific models, we can start to tease apart which tissues PIGA is important in and we can run modifier and drug screens to identify other interacting pathways and novel therapeutic targets.

In one of your works, you used pedigree analysis to identify potential protective modifier genes, including a null variant in CNTN2 – walk us through the process and tell us how you genetically validated CNTN2 as a target which could rescue most of the PIGA-associated phenotypes. What were your key findings and what are the future metabolic mechanisms remaining to be uncovered in this regard?

In our study, we used pedigree analysis in a family with variable expression of PIGA-CDG to identify potential protective genetic modifiers. Whole-genome sequencing revealed a null variant in CNTN2 that was present in asymptomatic carriers but absent in the probands. To test the interaction between PIGA and CNTN2, we used tissue specific Drosophila models where knockdown of the CNTN2 ortholog rescued key PIGA-related phenotypes like eye size, seizures, and motor defects. This showed that CNTN2 is a genetic modifier of PIGA, but the mechanism of interaction is still unclear. CNTN2 is a GPI-anchored protein, so it is possible the interaction could be broadly found across many GPI-anchored proteins. The interaction could also be CNTN2 specific and more related to its specific function in the nervous system.

Tell us about your work on evolutionary rates of glycosylation genes. What factors contribute to evolutionary rate differences among glycosylation genes – what are the consequences? How will identifying genetic modifiers of CDG enable our understanding of broad clinical spectrum seen in the patients? What tools have you used for these studies and what future studies should be done to expand these studies to develop targets for CDGs and other rare metabolic diseases?

We used evolutionary rate covariation (ERC) analysis to identify potential genetic modifiers of glycosylation genes. ERC is a computational method that identifies functionally related genes by measuring how similarly their evolutionary rates have changed across species over time. The more similar the evolutionary pattern, the more likely there is a genetic interaction. We discovered that glycosylation genes, particularly those involved in GPI anchor synthesis and N-linked glycosylation, exhibit high ERC values, indicating shared evolutionary pressures and functional interdependence. By identifying genes with high ERC to known glycosylation genes, we pinpointed potential modifiers that may contribute to the clinical variability observed in CDG patients. To validate these findings, we employed Drosophila models, confirming that several candidate genes modulate CDG phenotypes. Glycosylation affects many different genes and biological pathways. Modifier genes can help us to narrow down which pathways may be more important for CDG pathophysiology. Similar pipelines could be applied to other rare metabolic disorders in order to identify modifier genes and potential therapeutic targets.

Tell us about the unique experimental approaches you have taken throughout your work – what tools are you using, how difficult some of these experiments are – did you have to deal with midnight timepoints or require an army of undergrads/ long hours, had to use some un-conventional/creative tools to overcome experimental challenges?

Luckily using Drosophila there are a lot of readily developed tools. Most of the genetic constructs we needed had already been developed, and the different assays we ran are pretty common in the Drosophila world. While there were definitely quite a few weekends and long days, I managed to design my experiments so there were no midnight timepoints.

What are your upcoming plans? What metabolic pathways or signals do you aim to investigate further?

I just defended my PhD, so I will continue to work in the Chow lab as postdoc focusing on a more therapeutic targeted look at a new CDG. I’ll still be using natural genetic variation as an exploratory method, but with the hope of contextualizing and identifying therapeutic targets.

Your work intersects metabolism and genetic variation. How do these fields overlap and how do you integrate these disciplines in your research, and what unique insights have emerged from this approach?

Genetic variation plays a significant role in shaping metabolic function, as variants in metabolic genes can impact numerous interconnected pathways. In my research, I investigate how these genetic differences influence disease risk and severity, particularly by identifying modifiers that alter metabolic outcomes. This approach highlights the importance of studying disease within the context of diverse genetic backgrounds to better understand variability in clinical presentation and therapeutic response.

What role does curiosity play in your life, both within and outside of science? How important it is for you to answer basic science questions on metabolic signaling and how do you see its impact on animal health/relevance on human health?

I was definitely one of those kids that always asked a million questions, so I think my curiosity has really driven my work as a scientist. I think metabolism has such a huge impact on human health. Understanding these basic mechanisms is crucial, as they have direct relevance to human conditions like the rare diseases I study, and more common diseases such as diabetes, obesity, and cancer. Both in and out of the lab, curiosity keeps me asking meaningful questions and pushing for insights that can lead to real-world impact.

What changes have you seen in the scientific community in regard to studying these unique aspects of metabolic signaling in flies? Are we moving toward a more nuanced understanding, or do you see potential pitfalls?

Drosophila offers powerful tools to dissect conserved metabolic pathways in vivo, allowing for high-throughput and genetically precise studies. However, a potential pitfall is oversimplifying or overgeneralizing findings without considering species-specific differences—while flies are incredibly informative, translating insights to human biology still requires careful validation.

Tell us about how you see the future of metabolism evolve with the new upcoming tools – what techniques have you used and which tools are you most excited about?

I think ERC is an incredibly powerful and versatile tool—it can be applied to virtually any gene of interest to uncover new functional relationships and reveal previously unknown aspects of its biology.

Were there any pivotal moments that shaped your career path? What’s an unexpected place you’ve found inspiration for your work?

I’ve always had a passion for science, but I realized I wanted to pursue a PhD in genetics after a conversation with one of my undergraduate professors about her career path. She invited me to join her research lab—an opportunity I hadn’t previously considered—which ultimately opened the door to an entirely new trajectory for me. Rare disease remains an understudied area with immense potential for discovery. In particular, many metabolic rare disorders present rich opportunities for investigation through both computational and experimental approaches.

Tell us about what experiences/results/training motivated you to push forward in grad school?

I have been so lucky in joining the lab that I did. We are all great friends who help encourage each other to keep going. I definitely would not have made it through without the people in my lab.

How do you maintain a balance between your rigorous research activities and personal life? Are there hobbies or practices you find particularly rejuvenating?

The work-life balance is one of my favorite parts of doing grad school in Utah. I work right by the mountains, so all year long, I’m able to go hiking, rock climbing, and paddle boarding. And we frequently take weekend trips to one of the many national parks in the state. It’s always refreshing to get out in nature after a long day, and in Utah it’s so accessible.

If you hadn’t embarked on a career in biological research, what other profession might you have pursued, and why?

If I hadn’t studied science, I would have loved to open up a bakery. The method of baking is so therapeutic to me. I have always loved tinkering with recipes to try and find the best one.

Last week we learnt about the impact of environmental toxins on animal development and their resilient coping mechanisms from “genotypic” to “phenotypic” perspective. Check out the article – From shifting Skies to Toxic Tides (Lautaro Gandara)

Check out the article All the world’s a metabolic dance, and how early career scientists are leading the way !!

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