Researchers create first map of the spliceosome, an Achilles heel of cancer

It is a disconcerting fact that defies intuition: the 30 billion cells that make up a person share the same instruction manual, whether it is a neuron in the brain or a bone in the big toe. This common manual functions like an unusual cookbook, allowing each cell to prepare a different dish from the same recipe. Imagine the classic ingredients for paella listed on a page: rice, chicken, rabbit, saffron, garlic, oil, and so on. Each cell reads only a few select words, leading one to create paella, while another makes rabbit in garlic or rice with chicken. The same DNA yields different results, which is why a foot does not resemble a brain. On Thursday, a team of scientists from the Center for Genomic Regulation in Barcelona achieved a historic milestone by creating the first map of the intricate machinery responsible for this process: the spliceosome.

Geneticist Juan Valcárcel, 62, points out that in reality, the process is a little more complicated. “Words, as they are written in DNA, are separated by a bunch of meaningless letters. Cells have developed a machine, which I believe is the most complex they have, to eliminate those pieces that don’t make sense, in a process called splicing,” explains Valcárcel.

Following the same example, the DNA recipe would be written like this: rice osdlsdkjg chicken ugdlsgjls rabbit igosgsjodi saffron bpnemrac garlic efffeouu oil. The spliceosome machinery, made up of 150 proteins, splices out what doesn’t make sense: rice, chicken, rabbit, saffron, garlic, oil. And a second phenomenon, known as alternative splicing, selects only certain words: rice with chicken, rabbit with garlic.

Human DNA is a two-meter-long molecule folded within each cell. It is divided into approximately 20,000 sections known as genes, which contain the recipes for producing essential proteins for life, such as collagen in bones, hemoglobin for oxygen transport in the blood, and myosin in muscles. Thanks to the spliceosome’s work, human cells can produce 100,000 different types of proteins, despite having only 20,000 genes.

Valcárcel has been studying this intricate machinery since 1986. Reading errors in the spliceosome can lead to millions of cases of cancer, as well as rare and neurodegenerative diseases. Valcárcel’s team has spent over a decade producing the first map of the spliceosome, published on Thursday in the journal Science, which showcases the best research in the world. This machinery consists of 150 proteins, plus an additional 150 proteins that function as regulators on its exterior. The researchers meticulously deactivated each of the 300 proteins one by one to observe the effects. For their experiments, the authors utilized cells derived from Henrietta Lacks, a tobacco worker who died in 1951 in Maryland from uterine cancer.

“There is enormous potential,” says Valcárcel. “The really interesting thing is alternative splicing. The same gene can produce a protein that kills cells or another that inhibits cells from dying. Or proteins that make cancer cells proliferate a lot or not at all. If we understand these mechanisms, we can reverse these decisions or, with genetic engineering, make customized proteins,” says the geneticist. “This new work gives us a kind of functional map of the 300 components of the spliceosome. It tells us what they do in cancer cells when reading the messages from the genes.”

Valcárcel is sitting in a large meeting room in the building of the Centre for Genomic Regulation. Next to him is the Polish biologist Malgorzata Rogalska, 37, the lead author of the study. “Understanding the function and the structure are very different. The structure is a stable image in perfect conditions, but perfect conditions do not exist in our body. Understanding how the spliceosome adapts to different conditions is what has allowed us to draw up the first map,” says Rogalska.

The biologist compares splicing to the process of editing a film, where dozens of participants can take control and change the meaning of a scene. One of her main conclusions is that the 300 components of the spliceosome are so interconnected that the failure of one can trigger a domino effect. The researchers manipulated the SF3B1 component, whose mutations are linked to various types of cancer, including breast cancer, melanoma, and leukemia. Their experiment revealed that this alteration triggered a chain of errors that inhibited the growth of cancer cells.

“It is a potential Achilles’ heel that we can take advantage of to design new therapies. Our map offers a way to discover these weak points,” says Valcárcel. Her spliceosome map is now available to the scientific community.

Scientist Marina Serna, who has studied the structure of the spliceosome at the National Cancer Research Centre in Madrid, commends the accomplishment of her colleagues in Barcelona, although she did not take part in their research. “Splicing has fundamental implications in cancer,” she says. “This work has not only identified all the regulatory factors that, when altered, clearly affect the function of the spliceosome, but it has also revealed how these factors regulate themselves and each other in an extremely complex way. If you adjust one, it doesn’t affect just one other factor, it directly affects almost all the others.”

Serna underscores the scale of the challenge. A water molecule consists of two hydrogen atoms bonded to one oxygen atom (H₂O), while the formula for hemoglobin, the protein that gives blood its red color, is C₂₉₅₂H₄₆₆₄N₈₁₂O₈₃₂S₈Fe₄. The structure of a single protein is already intricate, but the spliceosome, with its 300 components, is even more formidable. “And the same protein has different conformations and interactions at various stages of the splicing cycle. The spliceosome is one of the most complex molecular machines known,” says the researcher

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