Ribosomes: a hidden key to understanding disease processes

Breaking new ground 12. sep 2023 3 min Professor and Group Leader Anders H. Lund Written by Morten Busch

The ribosome is the oldest known molecular machine that translates messenger RNA (mRNA) into proteins and has been considered a standardised workhorse. However, new findings show that different types of ribosomes produce different proteins, which can affect cell function and development. These discoveries have been reinforced by observations of cancer cells in which different types of ribosomes have been identified, opening the door to potential targeted therapy in combatting cancer and potentially also to generating specific types of cells for transplantation.

The ribosome is one of the oldest molecules known in the cell and reliably translates the mRNA templates it receives from the cell nucleus into proteins. This may explain why few researchers have been especially interested in investigating this process. Instead, the thinking has been that most of the irregularities and errors in the cell occur in producing the templates. This assumption is not true.

“Scientists have long known that ribosomes can differ slightly, but the assumption was that the ribosome will produce a protein based on whatever mRNA template you give it. However, our results suggest that different types of ribosomes produce different types of proteins. Since these ribosome variations are also present in human diseases, including cancer, we think that the new knowledge can help to understand what happens when cancer develops,” explains Anders H. Lund, Professor and Group Leader, Biotech Research & Innovation Centre (BRIC), University of Copenhagen.

The research has been published in Developmental Cell.

The same applies to people

The researchers’ interest in ribosomes was piqued several years ago when examining the DNA in a large sample of tumours and normal tissue from several types of cancer. The researchers found a specific group of RNA molecules that greatly increased in tumours compared with healthy tissue. Small nucleolar RNA (snoRNA) is a tiny fragment of RNA from the nucleus that is not translated into protein but nevertheless plays a key role in producing proteins.

“These snoRNAs seem to create changes in the RNA templates of other cells. These ribosomal RNA (rRNA) templates tell the cell how to construct the ribosome itself – meaning where protein synthesis takes place. These discoveries gave rise to the idea that cancer cells may have altered ribosomes, and sure enough, we showed that the ribosomes of cancer cells differ from those in other cells. Naturally, this begged the question as to why they differ,” says Anders H. Lund.

The results led the researchers to speculate that the changes might result from cancer cells needing specific proteins to grow, metastasise or undergo other types of development. This led them to consider why there are different types of ribosomes and how they are vital to the development of the body.

“We began by examining the brains of mice from the fetal stage and through their development, and the brain’s ribosomes actually change during this process, suggesting that ribosomal changes are necessary for normal development,” adds Anders H. Lund.

To investigate whether the same applies to people, the researchers also examined human stem cells.

“We induced the cells to differentiate into different types of cells and monitored them as they developed. We then determined whether the ribosomes had changed, and indeed they had,” explains Anders H. Lund.

Help to create the brain’s complexity

The researchers specifically focused on analysing a specific ribosome modification that might appear harmless. Using CRISPR technology, the researchers manipulated ribosomes in the stem cells with tiny chemical (methyl) groups in a process known as 2¢-O-methylation of rRNA.

“These tiny modifications have such a great effect that they change how stem cells develop and differentiate into brain cells,” says Anders H. Lund.

Remarkably, different brain regions showed unique modification profiles, suggesting the diverse role of the ribosome in maintaining the cellular mosaic that constructs brain complexity.

“We show both that ribosomes change during cell and tissue differentiation and that we can then influence the differentiation by recreating these changes. It has not previously been shown that the ribosome changes during early human development and that these changes are important for proper development,” explains Anders H. Lund.

May potentially inhibit or completely neutralise cancer

The ribosomes’ task is to translate the genetic code and create proteins. The code is carried from the cell nucleus to the ribosomes via mRNA. Many textbooks have said that ribosomes perform the same type of work with all mRNA – but they will probably need to be rewritten in this respect.

“The ribosome is not just a standardised machine. Our results primarily elucidate the biological processes that are crucial for developing specific types of cells, but this knowledge can also potentially be used to generate specific types of cells for transplantation. One of the greatest challenges in regenerative medicine is maintaining a specific type of cell development, which may result from the lack of attention and control of ribosome types,” says Anders H. Lund.

Anders H. Lund also thinks that the new knowledge can also open up new avenues for treating people with cancer, because cancer cells are already known to differ from normal cells in the types of ribosomes.

“By delving deeper into the complexity of ribosome heterogeneity, we hope to find new ways to manage various disorders that arise as a result of abnormal protein synthesis. Because ribosomes differ, we may be able to develop substances that can bind to and possibly inhibit or completely neutralise some of the many ribosomes in cancer cells,” concludes Anders H. Lund.

The aim of the laboratory is to unveil fundamental biological mechanisms and understand how these become perturbed during diseases, most prominently c...

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