Pit Head (c. 1930) William Heath Robinson
William Heath-Robinson was an English eccentric illustrator of ridiculously over-complicated solutions for (mostly) imaginary problems. His 'labour-saving' devices often took more people to operate them than the labour they saved.
His designs usually incorporated the most unlikely of objects, such as pianos or stacks of books to stand on, bent sticks to hold things up, pulleys and levers, held together with pieces of string, which never failed to have a knot in them because they had been made from shorter lengths tied together. And the amazing thing was, when you looked at them, it looked though they really would work, and if you took any component away, the whole thing would fail.
What he probably didn't appreciate at the time, was how closely his 'intelligent' designs resembled the designs of creationism's putative designer, but they are almost perfect metaphors for the detail beneath the superficial appearance of design in living organisms, especially the processes and mechanisms that look irreducibly complex.
Take, for example, a consequence of the failure of a 'Heath-Robinson' mechanism for correcting a problem with how RNA is built using templates in DNA which are scattered over several sections of DNA instead of being in a single, contiguous lengths. The different fragments of RNA that this initially produces must then be spliced together (just like William Heath-Robinson's pieces of string).
And of course, being a 'Heath-Robinson' machine, even this little section of the process of protein production is not simple. Splicing is a complex process involving the protein, RBFOX2, and when this fails in pancreatic cells, the resulting faulty RNA molecules can lead to cancer and metastasis of those cancer cells is itself facilitated by reduced RBFOX2.
How the failure of this correction mechanism causes pancreatic cancer was discovered by an international team of researchers led by Assistant Professor, Karen Mann, Ph.D., of the Department of Molecular Oncology, Moffitt Cancer Center, Tampa, FL, 33612, USA, with colleagues from The Tisch Cancer Institute; St. Jude Children’s Research Hospital; the Agency for Science, Technology and Research in Singapore; and the University of Otago in New Zealand.
Of course, the real problem here isn't with the designer but the mindless design process that produces these over-complicated, utilitarian 'Heath-Robinson' solutions to problems. DNA is RNA's data store and, so long as it works better than what went before it, there is no pressure to sort out and 'defrag' the DNA, so the irreducibly complex 'Heath-Robinson' machine might fail and cause pancreatic cancer occasionally, but the proteins the pancreas produces are worth the occasional failures, and mindless evolution has no concern for the suffering caused.
Here is how the team described their findings in Nature:
Abstract
RNA splicing is an important biological process associated with cancer initiation and progression. However, the contribution of alternative splicing to pancreatic cancer (PDAC) development is not well understood. Here, we identify an enrichment of RNA binding proteins (RBPs) involved in splicing regulation linked to PDAC progression from a forward genetic screen using Sleeping Beauty insertional mutagenesis in a mouse model of pancreatic cancer. We demonstrate downregulation of RBFOX2, an RBP of the FOX family, promotes pancreatic cancer progression and liver metastasis. Specifically, we show RBFOX2 regulates exon splicing events in transcripts encoding proteins involved in cytoskeletal remodeling programs. These exons are differentially spliced in PDAC patients, with enhanced exon skipping in the classical subtype for several RBFOX2 targets. RBFOX2 mediated splicing of ABI1, encoding the Abelson-interactor 1 adapter protein, controls the abundance and localization of ABI1 protein isoforms in pancreatic cancer cells and promotes the relocalization of ABI1 from the cytoplasm to the periphery of migrating cells. Using splice-switching antisense oligonucleotides (AONs) we demonstrate the ABI1 ΔEx9 isoform enhances cell migration. Together, our data identify a role for RBFOX2 in promoting PDAC progression through alternative splicing regulation.
Introduction
Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic cancer driven by oncogenic KRAS mutations and inactivation of tumor suppressor genes TP53, SMAD4, and CDKN2A. Importantly, these driver mutations are present in liver metastases1,2, the major site of disease dissemination and recurrence3,4,5, suggesting these events are necessary for disease maintenance. However, additional signaling, metabolic and regulatory processes contribute to disease progression. Recently, the regulation of RNA splicing has gained attention for its importance in cancer development, and initial analyses of splicing events in cancer have elucidated differential splicing signatures between tumor and normal tissue6,7,8, conserved splicing events across cancer types9,10, and the influence of alternative splicing events on therapy response.
RNA splicing is an integral biological process that regulates transcript stability and extends the repertoire of transcripts generated from a single genetic locus, contributing to a diversity of protein functions. Alternative splicing plays a major role in producing cell-type specific transcripts and is important for both maintaining embryonic stem cell (ESC) pluripotency and promoting cellular differentiation11,12,13,14. Regulation of alternative splicing is complex, involving conserved protein complexes inclusive of RNA binding proteins that direct the specificity of splicing events. In pancreatic cancer, individual splicing events have been linked to disease progression, patient survival, and response to chemotherapy15,16,17,18. Analysis of global RNA splicing signatures in pancreatic cancer using TCGA RNA-seq data identified enrichment of alternatively spliced transcripts in metabolic processes, cell-cell adhesion and cytoskeletal organization, suggesting alternative splicing in pancreatic cancer may impact processes important for cancer progression17,19. A study by Wang et al. identified a gene set in PDAC regulated at multiple levels by mutation, differential gene expression, and alternative splicing 20. While the importance of alternative splicing in controlling cell fate is well established in development, the role and regulation of alternative splicing in cancer and the biological functions of protein isoforms generated from alternately spliced transcripts are not well understood.
Previously, we performed a forward genetic screen in mice using Sleeping Beauty insertional mutagenesis to identify genes and processes important for promoting pancreatic cancer progression21,22. We identified an enrichment of genes encoding RNA binding proteins (RBPs), including Mbnl1, Mbnl2, and Rbfox2. MBNL1, MBNL2, and RBFOX2 have known roles in promoting alternative splicing of exons in transcripts associated with ESC pluripotency and differentiation. RBFOX2 coordinately regulates alternative splicing with MBNL1 in the differentiation of iPSCs 14. Further, RBFOX2 was identified as a key splicing regulator in ovarian and breast cancers responsible for the overlapping exon splicing patterns in these two cancers 8. Both cancer types exhibit RBFOX2 downregulation, either by transcriptional control in ovarian cancer or by alternative splicing in breast cancer, resulting in a reduction of the nuclear RBFOX2 isoform. The role of RBFOX2 in directing alternative splicing in pancreatic cancer is not known.
In this study, we uncovered a role for RBFOX2 as a tumor suppressor of pancreatic cancer metastasis in mouse models. Utilizing ex vivo and in vivo approaches, we defined a network of RBFOX2-controlled alternative splicing events linked to cytoskeletal remodeling and specifically associated exon-skipping in ABI1 with enhanced migratory potential and enrichment at the cell periphery of pancreatic cancer cells. These RBFOX2-mediated exon splicing events occur in pancreatic cancer patients, with differential splicing for a subset of splicing events observed across PDAC sub-types. Our studies link RBFOX2-associated alternative splicing of ABI1 to pancreatic cancer progression.
So, since an omniscient designer would have foreseen this problem and an omnibenevolent one would have designed a better one, or it knew exactly what it was designing and intended to cause pancreatic cancer, we can safely conclude one or more of the following:
- It isn't omniscient or omnibenevolent.
- It is malevolent
- It isn't involved in the 'design' of living organisms.
- It doesn't exist.
ID is not a problem for science; rather science is a problem for ID. This book shows why. It exposes the fallacy of Intelligent Design by showing that, when examined in detail, biological systems are anything but intelligently designed. They show no signs of a plan and are quite ludicrously complex for whatever can be described as a purpose. The Intelligent Design movement relies on almost total ignorance of biological science and seemingly limitless credulity in its target marks. Its only real appeal appears to be to those who find science too difficult or too much trouble to learn yet want their opinions to be regarded as at least as important as those of scientists and experts in their fields.
Available in Hardcover, Paperback or ebook for Kindle
This book presents the reader with multiple examples of why, even if we accept Creationism's putative intelligent designer, any such entity can only be regarded as malevolent, designing ever-more ingenious ways to make life difficult for living things, including humans, for no other reason than the sheer pleasure of doing so. This putative creator has also given other creatures much better things like immune systems, eyesight and ability to regenerate limbs that it could have given to all its creation, including humans, but chose not to. This book will leave creationists with the dilemma of explaining why evolution by natural selection is the only plausible explanation for so many nasty little parasites that doesn't leave their creator looking like an ingenious, sadistic, misanthropic, malevolence finding ever more ways to increase pain and suffering in the world, and not the omnibenevolent, maximally good god that Creationists of all Abrahamic religions believe created everything. As with a previous book by this author, "The Unintelligent Designer: Refuting the Intelligent Design Hoax", this book comprehensively refutes any notion of intelligent design by anything resembling a loving, intelligent and maximally good god. Such evil could not exist in a universe created by such a god. Evil exists, therefore a maximally good, all-knowing, all-loving god does not.
Illustrated by Catherine Webber-Hounslow.
Available in Hardcover, Paperback or ebook for Kindle
Illustrated by Catherine Webber-Hounslow.
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