In everyday life, unexpected outcomes can be frustrating. But in science, they often serve as the spark for groundbreaking discoveries. That’s precisely what happened when researchers at Memorial Sloan Kettering Cancer Center (MSK) teamed up with colleagues from the Icahn School of Medicine at Mount Sinai. Their surprising findings in the lab have paved the way for potential advancements in small RNA therapies, particularly in silencing genes linked to diseases like cancer.
“Sometimes you do an experiment thinking you’re testing one idea,” explains Dr. Eric Lai, a developmental biologist at MSK. “When it doesn’t go as planned, it can lead to something much more interesting.”
The Start of an Unexpected Discovery
The researchers, led by Dr. Seungjae Lee, a postdoctoral fellow in Dr. Lai’s lab, initially set out to study how a protein called ALAS1 contributes to the production of microRNAs — small regulatory RNAs that help control gene expression. Conventional wisdom suggested that removing ALAS1 from cells would decrease microRNA levels. But to their surprise, the exact opposite happened: microRNA levels increased.
This unexpected outcome revealed a previously unknown function of ALAS1, beyond its established role in producing heme, a molecule critical for oxygen transport, energy production, and other biological processes. Their findings, published in ‘Science’, provide new insights into ALAS1’s broader biological role.
Understanding Small RNA Molecules
MicroRNAs and their close relatives, small interfering RNAs (siRNAs), are tiny RNA fragments — just 21 to 22 nucleotides long. They bind to specific messenger RNAs (mRNAs) to suppress gene expression. Scientists have long harnessed this mechanism to develop siRNA-based drugs, which target and silence disease-causing genes.
The first FDA-approved siRNA drug, patisiran, emerged in 2018 to treat hereditary transthyretin amyloidosis, a genetic disorder. Since then, additional siRNA therapies have entered the market, and many more are undergoing clinical trials. These drugs hold promise for treating both rare and common diseases by interfering with the accumulation of problematic mRNAs.
ALAS1: More Than Meets the Eye
Dr. Lee’s experiments demonstrated that removing ALAS1 led to increased microRNA production. Interestingly, depleting other enzymes involved in heme synthesis didn’t affect microRNA levels, suggesting a unique “moonlighting” function for ALAS1 outside its usual role in heme production.
“We discovered that ALAS1 acts as a brake on microRNA production,” says Dr. Lai. “This unexpected role opens up exciting possibilities for enhancing siRNA therapies.”
Collaborating Across Disciplines
To extend their findings, the MSK team collaborated with Dr. Makiko Yasuda, Dr. Robert Desnick, and Dr. Sangmi Lee from Mount Sinai. These experts specialize in heme regulation and ALAS genes. Using custom animal models, they confirmed that removing ALAS1 in mouse liver cells resulted in a global increase in microRNAs. The researchers then explored whether this boost could enhance the efficacy of siRNA drugs.
“The idea is that by removing this brake, we might improve siRNA drugs’ ability to silence target genes,” explains Dr. Lai. This approach could potentially strengthen siRNA therapies targeting overactive genes, including oncogenes that drive cancer.
Toward Better siRNA Therapies
Currently, siRNA drugs face limitations. They primarily target liver cells, where drug delivery is relatively straightforward due to the liver’s natural filtration role. For instance, one siRNA drug, givosiran, safely targets ALAS1 to treat acute hepatic porphyrias. Building on this success, Dr. Lai’s team demonstrated that depleting ALAS1 in mouse liver cells enhanced the activity of a model siRNA compound.
This discovery raises the intriguing possibility of combining ALAS1-targeting agents with other siRNA drugs to boost their effectiveness. Enhanced siRNA therapies could reduce side effects by requiring lower doses, improve cost-efficiency, and potentially expand their use to other tissues beyond the liver.
The Broader Impact of Discovery Science
The journey of this research underscores the value of curiosity-driven science. Dr. Lai reflects on the contributions of his former mentor, Dr. Gary Ruvkun, who, alongside Dr. Victor Ambros, received the 2024 Nobel Prize for discovering microRNAs in the early 1990s. Interestingly, Dr. Ruvkun’s groundbreaking work didn’t begin with a focus on microRNAs. Instead, he was studying nematodes — tiny soil-dwelling worms — when he uncovered a completely new paradigm of gene regulation.
“This is a great example of how foundational research fuels transformative breakthroughs,” says Dr. Lai. “When people question why we fund research on model organisms like fruit flies or bacteria, it’s discoveries like this that provide the answer.”
As debates continue over funding priorities in science, Dr. Lai hopes the importance of basic research remains at the forefront. “Supporting foundational research is critical,” he says. “It’s the engine that drives innovation and leads to solutions for humanity’s biggest challenges.”
The discovery of ALAS1’s secret role in regulating microRNAs offers a promising avenue for advancing siRNA therapies. And it serves as a powerful reminder that in science, unexpected results often lead to the most exciting opportunities.
