One of the genes in the X chromosome pseudoautosomal regions is called SHOX. Patients with mutations in this gene have short stature. It is likely that this is also why patients with Turner’s syndrome tend to be short – they don’t produce enough SHOX protein in their cells. By contrast, patients with Trisomy X are likely to produce 50 per cent more SHOX protein than normal, which is probably why they tend to be tall[121].
It’s not just humans who have trisomies of the sex chromosomes. One day you may be happily amazing your friends with your confident statement that their tortoiseshell cat is female when they deflate you by telling you that their pet has been sexed by the vet and is actually a Tom. At this point, smile smugly and then say ‘Oh, in that case he’s karyotypically abnormal. He has an XXY karyotype, rather than XY’. And if you’re feeling particularly mean, you can tell them that Tom is infertile. That should shut them up.
Chapter 10. The Message is Not the Medium
Science commits suicide when it adopts a creed.
One of the most influential books on the philosophy of science is Thomas Kuhn’s The Structure of Scientific Revolutions, published in 1962. One of the claims in Kuhn’s book is that science does not proceed in an orderly, linear and polite fashion, with all new findings viewed in a completely unbiased way. Instead, there is a prevailing theory which dominates a field. When new conflicting data are generated, the theory doesn’t immediately topple. It may get tweaked slightly, but scientists can and often do continue to believe in a theory long after there is sufficient evidence to discount it.
We can visualise the theory as a shed, and the new conflicting piece of data as an oddly shaped bit of builder’s rubble that has been cemented onto the roof. Now, we can probably continue cementing bits of rubble onto the roof for quite some time, but eventually there will come a point when the shed collapses under the sheer weight of odd bits of masonry. In science, this is when a new theory develops, and all those bits of masonry are used to build the foundations of a new shed.
Kuhn described this collapse-and-rebuild as the paradigm shift, introducing the phrase that has now become such a cliché in the high-end media world. The paradigm shift isn’t just based on pure rationality. It involves emotional and sociological changes in the psyches of the upholders of the prevailing theory. Many years before Thomas Kuhn’s book, the great German scientist Max Planck, winner of the 1918 Nobel Prize for Physics, put this rather more succinctly when he wrote that, ‘Scientific theories don’t change because old scientists change their minds; they change because old scientists die[122].’
We are in the middle of just such a paradigm shift in biology.
In 1965, the Nobel Prize in Physiology or Medicine was awarded to François Jacob, André Lwoff and Jacques Monod ‘for their discoveries concerning genetic control of enzyme and virus synthesis’. Included in this work was the discovery of messenger RNA (mRNA), which we first met in Chapter 3. mRNA is the relatively short-lived molecule that transfers the information from our chromosomal DNA and acts as the intermediate template for the production of proteins.
We’ve known for many years that there are some other classes of RNA in our cells, specifically molecules called transfer RNA (tRNA) and ribosomal RNA (rRNA). tRNAs are small RNA molecules that can hold a specific amino acid at one end. When an mRNA molecule is read to form a protein, a tRNA carries its amino acid to the correct place on the growing protein chain. This takes place at large structures in the cytoplasm of a cell called ribosomes. The ribosomal RNA is a major component of ribosomes, where it acts like a giant scaffold to hold various other RNA and protein molecules in position. The world of RNA therefore seemed quite straightforward. There were structural RNAs (the tRNA and rRNA) and there was messenger RNA.
For decades, the stars of the molecular biology catwalk were DNA (the underlying code) and proteins (the functional, can-do molecules of the cell). RNA was relegated to being a relatively uninteresting intermediate molecule, carrying information from a blueprint to the workers on the factory floor.
Everyone working in molecular biology accepts that proteins are immensely important. They carry out a huge range of functions that enable life to happen. Therefore, the genes that encode proteins are also incredibly important. Even small changes to these protein-coding genes can result in devastating effects, such as the mutations that cause haemophilia or cystic fibrosis.
But this world view has potentially left the scientific community a bit blinkered. The fact that proteins, and therefore by extension protein-coding genes, are vitally important should not imply that everything else in the genome is unimportant. Yet this is the theoretical construct that has applied for decades now. That’s actually quite odd, because we’ve had access for many years to data that show that proteins can’t be the whole story.
Scientists have recognised for some time that the blueprint is edited by cells before it is delivered to the workers. This is because of introns, which we met in Chapter 3. They are the sequences that are copied from DNA into mRNA, but then spliced out before the message is translated into a protein sequence by the ribosomes. Introns were first identified in 1975[123] and the Nobel Prize for their discovery was awarded to Richard Roberts and Phillip Sharp in 1993.
Back in the 1970s scientists compared simple one-celled organisms and complex creatures like humans. The amount of DNA in their cells seemed surprisingly similar, considering how dissimilar the organisms were. This suggested that some genomes must contain a lot of DNA that isn’t really used for anything, and led to the concept of ‘junk DNA’[124] – chromosome sequences that don’t do anything useful, because they don’t code for proteins. At around the same time a number of labs showed that large amounts of the mammalian genome contain DNA sequences that seem to be repeated over and over again, and don’t code for proteins (repetitive DNA). Because they don’t code for protein, it was assumed they weren’t contributing anything to the cell’s functions. They just appeared to be along for the ride[125][126]. Francis Crick and others coined the phrase ‘selfish DNA’ to describe these regions. These two models, of junk DNA and selfish DNA, have been delightfully described recently as ‘the emerging view of the genome as being largely populated by genetic hobos and evolutionary debris[127]’.
We humans are remarkable, with our trillions of cells, our hundreds of cell types, our multitudes of tissues and organs. Let’s compare ourselves (a little smugly, perhaps) with a distant relative, a microscopic worm, the nematode Caenorhabditis elegans. C. elegans, as we usually call it, is only about one millimetre long and lives in soil. It has many of the same organs as higher animals, such as a gut, mouth and gonads. However, it only consists of around 1,000 cells. Remarkably, as C. elegans develops, scientists have been able to identify exactly how each of these cells arises.
This tiny worm is a powerful experimental tool, because it provides a roadmap for cell and tissue development. Scientists are able to alter expression of a gene and then plot out with great precision the effects of that mutated gene on normal development. In fact, C. elegans has laid the foundation for so many breakthroughs in developmental biology that in 2002 the Nobel Committee awarded the Prize in Physiology or Medicine to Sydney Brenner, Robert Horvitz and John Sulston for their work on this organism.