Holiday Reading (1) – Molecular Dominoes

As our faithful readers know, the idea in these pieces is to keep up to date with what seem to me to be significant steps along the cancer pathway – a sort of bullet point follow-up to Betrayed by Nature. There’s no doubt that all this keeping pace with exciting developments is great fun but it can leave you a bit breathless – or maybe even worse, liable to loose touch with the basics. So, although this may not be for everyone, I thought it might help some (including me) to take a deep breath and have a couple of items on what you might call “The Story So Far.”

Accordingly, this and the next three posts will be a recap – even better a refresher – a gentle think about the problem that is cancer and how we’re doing. And before you say ‘after umpteen essays’ (96 to be precise but who counts when you’re having fun?) ‘this sounds a bit cart before the horse-ish’ let me just emphasise that the ‘horse’ was really Betrayed by Nature.

Molecular Dominoes

It is now 43 years since President Richard Nixon signed the National Cancer Act, thereby launching what has frequently been referred to as the ‘war on cancer’ in which prodigious sums of money have been committed to the cause of understanding cancer biology and thereby developing more effective treatments. The aim of this is, of course, to eliminate cancers as a major cause of death. It is debatable, to say the least, whether this largesse would have been distributed with quite such gusto had the crystal ball been peered into with sufficient intensity to reveal that in 2015 well over half a million Americans will die from cancers.

That does not sound like an unmitigated success story – nor is it – but the immense amounts of perspiration, sprinkled with the odd moment of inspiration, that have gone into cancer research have yielded a staggering amount of information. Fuelled in particular by the astonishing technical revolution that permits the complete DNA sequences of human genomes (i.e. the genetic code) to be obtained within a day or so, we can now survey in extraordinary detail the molecular basis of this diverse ensemble of diseases that are driven by the acquisition of mutations in components that regulate the fundamental processes of life.

A major objective of all this industry is, of course, to come up with drugs that complement or, ideally, replace surgery and radiotherapy for the treatment of cancers. It’s nearly seventy years since the Buffalo-born pathologist Sidney Farber, working at the Harvard Medical School, launched this odyssey and the intervening period has seen stunning triumphs with remission rates for some formerly untreatable cancers now at nearly 100 percent. But one of the most amazing revelations of all has been the facility with which cancers manage to circumvent drugs designed to kill them. The upshot is that drug resistance is a major limitation to the effectiveness of chemotherapy and most cancer deaths occur because cells outwit the available drugs.

The saga of how tumour cells manage to be so adept at evading mankind’s efforts to skewer them is both fascinating and relevant to all. Like every good story it has a beginning and a middle, which is pretty well where we are at the moment. It will also have an end – although opinions are divided as to what that will be.

In the beginning: Getting the message across

All animals are created and maintained by chemical signals (messengers) telling individual cells what to do. For example: make more cells (proliferate)/make a different type of cell/move to a different location/do nothing/die. Once a messenger contacts the surface of a cell it sets off a game of molecular dominoes: relays of proteins are activated that transfer a signal to the nucleus – specifically to the machinery that reads the coding sequence of genes within DNA and transforms that into proteins. Proteins are the machines of life: workhorses that make things happen so that vast clumps of cells (i.e. living organisms like us) behave in a coordinated fashion.

The signal pathways within cells are complex: best not to Google ‘signalling pathways’ as you’ll be presented with a jumble looking for all the world like a map of the Tokyo subway. But essentially they’re linear stepping stones from membrane to nucleus so it’s convenient to think of them as a telephone system – hundreds of callers (messengers) being put through to the appropriate receivers, i.e. gene targets. Convenient but somewhat misleading as life is rather more complicated. The reason for this is that cells (and with them life) have evolved on a trial and error basis. No bearded electronics whizzo up in the blue yonder sat down with a pencil and paper and designed the ‘best’ circuits that were then assembled in some celestial workshop to remain fixed for all time. Instead we are the result of what in Betrayed by Nature I called the ‘genetic roulette’ of Darwinian evolution. Our signalling pathways resemble the wiring in an old house that has been modified, extended and tweaked by successive owners over many decades. New lights here, a replacement phone line there, etc. with the old cables being disconnected but left in the walls. Animals are much the same except that their redundant wiring accumulates in their genomes, unrequired but lurking and occasionally capable of being reactivated.

Text scheme

Diverse chemical signals activate multiple pathways within cells, ultimately regulating the machinery that reads the genetic code carried by DNA in the nucleus.

These pathways could be thought of as domino runs of different proteins (colored boxes) tripped by the molecular switch of messenger binding to receptor. Rather than acting in isolation, pathways may diverge and/or converge and components may interact, directly or indirectly, giving rise to ‘cross-talk.’ The whole assembly is thus best thought of as a signalling network.

That will do for now: next time we’ll look at what can go wrong.