An evolutionary hiccup
It’s well known that tracing our family tree back 400 million years reveals a fishy past. This history is enshrined in our DNA in the pattern of nerves that control breathing. From time to time that control throws a wobbly in the form of involuntary spasms of the diaphragm manifested as a fit of hiccups – what the medics call singultus, which in Latin means sobbing – readily brought on by contemplating a comprehensive map of intracellular signalling pathways. Hiccups, however, are caused, as Neil Shubin, in his wonderful book Your Inner Fish has explained, by a mis-firing neuron in our brain stems that produces the type of electric signals that control the regular motion of amphibian gills. A genetic recipe hoarded in the nuclear loft is inadvertently recalled. For the most part this result of DIY evolution is no more than mildly embarrassing, although the poor fellow who made the Guinness Book of Records by hiccupping for 68 years may have used a stronger term.
As we’re really talking about cancer, we should mention that persistent spasms of hiccups and difficultly swallowing may be indicators of esophageal cancer, where a tumour in the gullet (the tube connecting the back of the mouth to the stomach) grows into the trachea and flips the hiccup switch by mechanical pressure.
Je pense, donc je suis un blanc-manger
Whilst the key feature of all these pathways is that they connect the outside world to the nucleus of a cell, it’s become clear that each pathway does not exist in isolation. Individual pathways can talk to each other – sometimes called cross-talk – individual domino runs intersecting, if you like. So evolution has cooked up thousands of proteins floating around in our cells that can be mapped into discrete signal pathways but, in the molecular jostle of the cell, each may affect any of the others – if not directly then via just a few intermediates. To avoid the Tokyo subway syndrome it’s easiest to think of the cell as a blancmange: poke it anywhere and the whole thing wobbles.
The complex network of signalling pathways in cells.
Left: the dots represent proteins that inter-communicate (lines) – best thought of as a blancmange.
Why is grasping this picture of what seems like a molecular madhouse important? Well, one thing we should bear in mind is that the set-up may look chaotic to us but our cells somehow make perfect sense of it all because they take clear decisions as to what to do. But the reason for grappling with it at all, other than to be humbled by our ignorance, is that these signal systems are a major target for anti-cancer drugs. To be more precise, it’s disruptions in these proliferation-controlling pathways, caused by mutations, at which we take aim with the contents of our drug cocktail cabinet.
What goes wrong in cancer?
If you want a three word definition of cancer ‘cells behaving badly’ will do fine. If you insist on being scientific ‘abnormal cell proliferation’ covers it nicely, meaning that control of cell replication has been overcome to the extent that cells reproduce more rapidly than they should or at an inappropriate time or in the wrong place. Underlying this abnormal behaviour is damage to DNA, that is, mutations. This remains true even if the initial cause does not directly affect DNA. It’s estimated that about 20% of the global cancer burden comes from infections, mainly in contaminated drinking water. These can cause chronic inflammation that eventually leads to mutations and thence to cancer. Other factors, for example, tobacco smoke and radiation, can directly damage DNA and about 10% of cancers are set off by what you might call a taxing inheritance – mutations already present in DNA at birth.
The capacity for high-throughput sequencing of complete human genomes has spawned ambitious projects that include Genomics England’s sequencing of 100,000 genomes by 2017 and The Cancer Genome Atlas that aims to provide a mutation data base for all the major cancers. One of the most mind-boggling facts that has already emerged from this revolution is the extent of disruption that can occur in the genomes of cancer cells: as many as one hundred thousand mutations within one cell. For the sake of completeness we should note that, cancer being cancer, the mutational spectrum is astonishing and, at the other end of the scale, there’s a childhood leukemia that results from just one change to DNA and there’s a type of central nervous system tumour that appears to develop without any mutations at all. For the most part, however, cancer cells carry a mind-boggling number of mutations and the assumption, nay hope, is that the vast majority of these changes are ‘passenger’ mutations that do not affect cellular behaviour: they’re a by-product of the genetic mayhem characterizing cancer cells. The ones that count are ‘driver’ mutations that can arise in any of several hundred of our 20,000 or so genes, changing the activity of the proteins they encode to contribute to cancer development. Only a small number (half a dozen or so), of these drivers, acting together, is required for cancer to emerge. Thus, although only a relatively small group of ‘drivers’ is needed, almost limitless combinations can arise.
The accumulation of mutations takes time, which is why cancers are largely diseases of old age: two thirds of them only appear in people over the age of sixty. The estimate is that if we lived to 140 everyone would get cancer but, pending that happy day, when or whether the disease manifests itself in an individual is indeed a matter of genetic roulette – genetic evolution within cancer cells. So wonderful has the technology become we can now inspect individual cells in tumours to reveal that driver mutations occur in single cells that can expand to form groups of cells, called clones. These multiple clones can modulate their mutational profile independently and, as a result, proliferate at different rates. So you can picture tumours as a complex patchwork of genetically related, competing clones. In other words, as we’ve suspected all along, cancers are a form of dynamic Darwinism.
The critical point is that key mutations drive cancer and they do so by upsetting the normal working of signal pathways that control whether cells proliferate or not. You could say it’s Nature poking the blancmange but these are delicately selected pokes – the product of the evolution of a cancer’s genetic signature – that just tweak signalling mechanisms enough to make cells a little more likely to multiply. In coming up with drugs that target specific mutations we’re giving the blancmange another poke – the aim being, of course, to prod it back to normality.
An obvious question
Having mentioned that, albeit very rarely, cancers emerge that don’t seem to be driven by changes in the sequence of DNA – how do they do that? The answer lies in epigenetic modifications – any modification of DNA, other than in the sequence of bases, that affects how an organism develops or functions. They’re brought about by tacking small chemical groups either on to some of the bases in DNA itself or on to the proteins (histones) that act like cotton reels around which DNA wraps itself. In effect this makes the DNA more difficult to get at for the molecular machines that turn the information in genes into proteins. So these small chemical additions act as a kind of ‘super switch’ that can, for example, block genes that act as brakes on cell proliferation – hence promoting cancer.
Neil Shubin Your Inner Fish, Random House, 2008.