The Film Editors Inside Our Cells! Dr. Soo-Chen Cheng’s Research on RNA Splicing

Recalling forty years ago, Soo-Chen Cheng was still a fourth-year student in the Department of Chemistry at National Taiwan University, undertaking a research project under Dr. Tung-Bin Lo (羅銅壁) with echidnotoxin as the material. “This is very different from doing chemistry experiments; it feels more connected to life, and there are many natural mysteries waiting to be explored!” Soo-Chen Cheng recalled the days she came to love biochemical experiments.

Forty years have passed, and Soo-Chen Cheng is still devoted to fundamental research; it’s just that her subject is no longer echidnotoxin, but the mysteries of RNA splicing within organisms.

The ‘Editing’ Inside Our Bodies

The godfather of film editing, Walter Murch, once said, “The best editing is as seamless as a blink of an eye.” In the natural world, a similar feat of seamlessness occurs constantly: countless acts of “RNA splicing” are taking place in our bodies, many in the blink of an eye—or even faster.

To understand RNA splicing, we must first grasp a fundamental principle of biology known as the Central Dogma, which describes the flow of genetic information from DNA to protein.

Numerous proteins in the human body are required for a variety of functions, such as metabolism, muscle contraction, and immune responses. The genetic blueprints for these proteins are encoded in our DNA within segments known as genes. Each gene is typically divided into two kinds of sections: exons and introns.

During RNA splicing, the introns are cut out and discarded, while the exons are spliced together. These joined exons form the final blueprint: a mature messenger RNA (mRNA) molecule. This mRNA then directs the translation of a specific protein, which goes on to perform its designated function within the organism.

All of the exons in the human genome—the segments of DNA that actually code for proteins—make up a surprisingly small 1.5% of our total DNA. This raises some critical questions: How can such a tiny fraction of the genome produce the vast and complex array of proteins found in the human body? And furthermore, why is it that sometimes, even when the DNA sequence of these exons appears perfectly normal, the body still produces faulty proteins that lead to disorders and genetic diseases?

The Art of Precision: Knowing What to Keep and What to Cut

“Editing, after all, is an art largely achieved by subtraction, by a negation of those elements that do not serve the final product. More often than not, that shape is determined as much by what is taken out as what is left in.”

— Justin Chang, FilmCraft: EDITING

This core principle extends beyond the film editing room; it is also fundamental to the process of RNA splicing within our bodies. The diagram below helps to visualize how RNA is processed into mRNA.

The initial gene segments of RNA are like the clips filmed from the DNA movie script. The spliceosome acts as the team of film editors in organisms, selecting and assembling the necessary clips to create a coherent storyline. Any unwanted footage is discarded, much like introns being removed.

If a mistake occurs during this editing process—resulting in missing or extraneous clips—the movie’s plot becomes incoherent. This jumbled film is analogous to a faulty protein produced at the end of the biological process. Such a protein disrupts the body’s normal physiological functions, leading to disorders or genetic diseases.

Mapping the RNA Splicing Pathway

To understand where errors in RNA splicing occur, we first need a complete map of the splicing pathway. Using the budding yeast Saccharomyces cerevisiae as a model organism, Dr. Cheng’s team applied biochemical methods to dissect this process step-by-step. Their research identified the specific “film editors”—the protein factors and complexes—that participate in the reaction.

But can yeast, a simple single-celled organism, really help us understand the human body? Dr. Cheng explains that RNA splicing is a fundamental biochemical reaction in all eukaryotes, and its core mechanism is highly conserved across species. While humans are vastly more complex than yeast, our genome has only about four times as many genes.

Our current understanding of the RNA splicing pathway, built upon years of dedicated research by numerous teams, is summarized in the diagram below. In simple terms, the process unfolds in four main phases: assembly, activation, catalysis, and disassembly. Throughout this process, “the film editors of RNA splicing”—composed of five small nuclear RNAs and a host of protein factors—carries out the complex task of splicing.

During RNA splicing, different factors play specific roles. Some protein factors are responsible for bringing the exons into close proximity to facilitate their covalent bonding. Other protein complexes, like the NTC, activate the molecular mechanisms and catalyze the splicing reaction. Finally, complexes such as the NTR manage the crucial degradation phase, allowing the protein factors to be recycled for subsequent rounds of splicing.

At the beginning, no one knew about the existence and the functions of these protein complexes, NTC and NTR, and these protein factors, Cwc22, Cwc24, Cwc25, Yju2 and so on, until Dr. Cheng’s research team broke down the process of RNA splicing step by step through biochemical experiments, and finally discovered “the film editors of RNA splicing” participating in the reaction.

Under natural conditions, the splicing process can still go wrong. For instance, if splicing factors become stalled on gene segments of RNA, they are no longer available to process new RNA, which will cause negative effects on the cell. To use the film analogy: if the entire editing team gets stuck on a single, problematic movie project and makes no progress, the production schedule for all subsequent films will inevitably be delayed.

RNA Splicing Research: The Story Continues…

This line of research demands repeating experiments, meticulously monitoring their outcomes, and using creative inference to deduce the cause of any changes. While time-consuming and laborious, Dr. Cheng believes that “experimental procedures must be rigorous to yield reliable results.” Research teams can face seemingly insurmountable obstacles, “but the greatest joy in research,” she says, “is when you finally solve a problem you’ve been pondering for a long time!”

Many genetic diseases are linked to errors in RNA splicing. However, to develop targeted drugs, scientists must first have a complete understanding of the splicing pathway’s mechanisms. In a thrilling development in late 2016, the U.S. Food and Drug Administration (FDA) approved a medication for Spinal Muscular Atrophy (SMA). This drug is able to correct and modulate the abnormal RNA splicing of a critical motor neuron protein. Dr. Cheng notes that this success was built on more than two decades of relentless research by this foreign team, in collaboration with biotech and pharmaceutical companies.

Beyond the inspiring success of the SMA drug, another breakthrough is illuminating the future of RNA splicing research.

In the past, scientists could only hypothesize about the RNA splicing pathway through biochemical experiments. In recent years, however, major advances in cryo-electron microscopy (cryo-EM) have made it possible to resolve the complex structures of splicing complexes, revealing the intricate details of the spliceosome at different stages. This is equivalent to directly “seeing” the RNA splicing process, and it has confirmed many earlier experimental hypotheses. This progress has brought immense excitement to researchers, as the spliceosome’s complexity and dynamic nature once made its structure seem impossible to analyze.

“Many of the founding pioneers in this field are now in their eighties,” Dr. Cheng says, her own eyes filled with excitement. “They never imagined they would live to see these structures with their own eyes. They are overjoyed!”

At this very moment, RNA splicing is constantly at work within our bodies. Although this field has yielded numerous discoveries, vast frontiers remain unexplored. Ultimately, the more we unravel the complexities of the spliceosome, the better equipped we will be to combat the diseases caused by splicing defects.