In the central nuclei (blue) of immune cells called macrophages, removing the WASP gene (as in the right panel) leads to fewer clusters of RNA splicing proteins (red).
Credit: Xuan Zhou of KAUST
Wiskott-Aldrich syndrome is just one of a whole host of childhood diseases that have a genetic basis and which any decent scientific theory should be capable of explaining, if not yet devising a cure for them. For creationists however, they present a special problem if they are to stick to their dogma that nothing happens at the level of the genome that isn't the specific will and intent of their putative designer god.
This is especially relevant now that scientists working at the Salk Institute, La Jolla, CA, USA and King Abdullah University of Science and Technology (KAUST), Saudi Arabia have discovered the underlying cause of this rare and distressing childhood disorder. As the Salk Institute press release describes it:
This study not only suggests new targets for treating Wiskott-Aldrich syndrome with small molecule drugs, but also sheds new light on the basic biology of RNA splicing, an important and not fully understood process.
These RNA splicing factors could both be a biomarker for monitoring Wiskott-Aldrich syndrome, and a potential target for treatment.
Professor Juan Carlos Izpisua Belmonte, corresponding author
Gene Expression Laboratory
Salk Institute, La Jolla, CA, USA
Gene Expression Laboratory
Salk Institute, La Jolla, CA, USA
Babies with Wiskott-Aldrich syndrome begin to develop symptoms quickly after birth: itchy, scaly rashes, frequent bruises and nose bleeds are some of the first signs. Over time, they become prone to infections and are more likely than other children to develop autoimmune diseases and cancers. The only potential cure is a bone marrow transplant, which carries a host of complications and only works in some children.The underlying mechanism concerns how cells normally cut and paste strands of RNA in a process called RNA splicing. RNA splicing is often needed because a 'gene' may be composed of non-contiguous segments of DNA separated by various lengths of non-coding DNA. The entire section gets translated into RNA which then needs these 'introns' removed and the RNA spliced together to form a template for the protein, before it can be transcribed. In Wiskott-Aldrich syndrome, a genetic mutation disrupts this process which in turn means that numerous immune and anti-inflammatory proteins are not made properly.
The SALK Institute press release continues:
Scientists have long known that Wiskott-Aldrich syndrome is caused by mutations in a gene on the X chromosome; the gene and the protein it encodes were named WASP after the syndrome. The WASP protein is found throughout cells in the blood and immune system, and one of its functions is to maintain these cells’ cytoskeletons, the microscopic networks of proteins that give cells their shape and organization. But changes to the cytoskeleton couldn’t explain all the symptoms.
Former Salk Postdoctoral Fellow Mo Li, now the head of KAUST’s Laboratory of Stem Cell and Regeneration, and Izpisua Belmonte wondered if WASP plays other roles—particularly in the nuclei of blood and immune cells, where genetic material is stored and processed.These are powerful models that can help us understand how WASP functions and what the underlying cellular mechanisms of Wiskott-Aldrich syndrome are.
Bo Li, co-author
Bioscience Program,
Biological and Environmental Science and Engineering Division,
King Abdullah University of Science and Technology (KAUST),
Thuwal, Kingdom of Saudi Arabia
To find out, they removed the WASP gene from stem cells and coaxed the cells to become macrophages or B cells, two types of immune cells impacted by the disease. They also collected cells from two patients with Wiskott-Aldrich syndrome and generated induced pluripotent stem cells (iPSCs) containing the disease-associated mutations in WASP. Then they compared the altered cells to normal macrophages and B cells.
Immune cells lacking WASP, or containing mutations in the WASP gene, appeared different right away; there were many more clusters—known as nuclear speckles—in the centers of diseased cells. For a protein to be produced by a cell, the DNA encoding it is first transcribed into a strand of RNA. Often, this initial strand contains more genetic material than is needed; this is where RNA splicing comes in. Proteins in nuclear speckles cut and paste bits of the initial RNA strand into its final instructions for a protein.When we saw differences in the nuclear speckles of these cells, this is the first time we realized that WASP might be involved in RNA splicing.
Baolei Yuan, first author
Bioscience Program,
Biological and Environmental Science and Engineering Division,
King Abdullah University of Science and Technology (KAUST),
Thuwal, Kingdom of Saudi Arabia
The researchers also showed that many proteins related to RNA splicing were present at higher levels in the cells lacking WASP or with mutations in WASP. WASP both controlled the production of these RNA-splicing factors and directly played a role in RNA splicing itself. The team pinpointed thousands of other genes with altered RNA splicing—many were related to inflammation, autoimmunity and cancer.
Additional experiments revealed that repairing WASP mutations fixes these RNA splicing defects. What’s more, lowering levels of an RNA-splicing factor, SRSF2, can prevent the problems. These results suggest that drugs targeting SRSF2 could treat Wiskott-Aldrich syndrome in humans, the researchers say.
More technical detail is given in the abstract to the team's open access paper published recently in Nature Communication:
AbstractClearly then, this is a complex process of the sort that intelligent [sic] design creationists insist can only be the work of a supernatural designer, and yet here we have an example, just one of many, where the process goes wrong and fails to work as 'designed'. From an intelligent [sic] design perspective, there can only be two reasons for this failure of a process designed by an omniscient, perfect, designer. They are:
The diverse functions of WASP, the deficiency of which causes Wiskott-Aldrich syndrome (WAS), remain poorly defined. We generated three isogenic WAS models using patient induced pluripotent stem cells and genome editing. These models recapitulated WAS phenotypes and revealed that WASP deficiency causes an upregulation of numerous RNA splicing factors and widespread altered splicing. Loss of WASP binding to splicing factor gene promoters frequently leads to aberrant epigenetic activation. WASP interacts with dozens of nuclear speckle constituents and constrains SRSF2 mobility. Using an optogenetic system, we showed that WASP forms phase-separated condensates that encompasses SRSF2, nascent RNA and active Pol II. The role of WASP in gene body condensates is corroborated by ChIPseq and RIPseq. Together our data reveal that WASP is a nexus regulator of RNA splicing that controls the transcription of splicing factors epigenetically and the dynamics of the splicing machinery through liquid-liquid phase separation.
Yuan, B., Zhou, X., Suzuki, K. et al.
Wiskott-Aldrich syndrome protein forms nuclear condensates and regulates alternative splicing.
Nat Commun 13, 3646 (2022). https://doi.org/10.1038/s41467-022-31220-8
Copyright: © 2022 The authors. Published by Springer Nature Ltd.
Open access
Reprinted under a Creative Commons Attribution 4.0 International license (CC BY 4.0)
- A mistake - but of course that can be ruled out because a perfect, omniscient designer could not have made a mistake.
- Intent - the designer intended the process to go wrong in random children and cause them unnecessary suffering and distress, and probably shortening their lives.
Creationists are forbidden by dogma and as a condition of cult membership, to explain this as the result of a mindless, natural process, so perhaps one of them can pluck up the courage to say which of the only two possible explanations they would prefer - incompetence or malevolence. I've been issuing that challenge or something very similar for several years now and have never once had an intelligible answer.
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