Socrates and apoptosis

In the fourth of five articles short-listed for the ICR's Mel Greaves Science Writing Prize 2015, Dr Daniel Nava Rodrigues offers similarities between our bodies and city-states – how are the cells in our bodies policed?

Plato writes that the day before Socrates drank hemlock he had a chat with Crito, who begged him to escape. In the dialogue that follows this plead, Socrates patiently explains to his friend why escaping was not an option. As a free man of Athens, raised and nurtured by the city, he had accepted “the covenants and agreements” of being an Athenian. To flee his death sentence would be a betrayal of the polis that brought him into existence and thus an insult to every other civilised city. It would be “returning evil for evil, and injury for injury”. Socrates would have none of it.

The human body is a polis, a community of ten trillion cells with hundreds of distinct roles. It is thought this multicellular covenant was a bargain struck some 1.5 billion years ago between single celled individuals living in colonies. It laid down the rules for interactions and a division of labour. Somatic cells would be in charge of protecting and feeding the colony whilst germ cells would spread the colony’s genetic legacy. To ensure compliance of every member to this social contract, a clockwork ballet of biomolecules directs cellular behaviour. Changes in choreography determine whether daughter cells acquire a particular shape and specialty, ceasing to divide, or retain the ability to self-replicate.

But why would any cell give up its capacity to multiply indefinitely? What survival advantage would that individual cell have? The answer is clear: none. However, if evolution is seen from the perspective of the genes replicating in cells, the multicellular covenant has its advantages. Due to sheer size for example, these cell aggregates would have been better able to resist an attack from marauding unicellular predators and pass on their genes. Likewise, specialised tissues acting as a team could survive a wide range of environments, which increased the chances that their DNA would be passed on. Bodies are mere vessels for the truly interested party, the genes. The end result is that humans share about 60% of their genes with a fruit fly. Species come and go, but most genes essential for cell survival and for the maintenance of the multicellular covenant, and thus for the perpetuation of the genes themselves, have been around for hundreds of millions of years.

Cancer is a breach of the multicellular deal and mutations – changes in DNA sequence – are a crucial part of the disease. Mutations disturb the well-behaved dance of signals and counter-signals transforming it into a mosh pit of nonsense. Cancer cells abandon the group-effort and revert to the individualistic behaviour that predominated during the first few billion years of life on earth. But how do mutations come about? Exposure to UV light, tobacco smoke, and asbestos are all well recognised mutagens – they promote mutations. However, absent any external insults, replication of DNA is simply not a fail-proof process and mutations are a fact of life. Indeed, they are the driving force of evolution and generate the innovations that natural selection sorts out. What is truly astonishing, given the sheer number of cell divisions over the decades long lifespan of a human is that some of us never develop a tumour at all!

How come? Well, the fact of the matter is that most of us do develop mutations in our cells, but most of these cells don’t go very far. Among the cadre of gene survivors we have inherited from our ancestors, some are dedicated to the maintenance of the genome. Again, if genes exist for the purpose of self-perpetuation, it makes perfect sense that self-preservation mechanisms would have been selected. Or put another way, ancestors whose cells did not have tumour-suppressing mechanisms would too readily have generated offspring willing to break the covenant and go rogue. But if mutations are inevitable, what’s the solution? Faced with DNA damage, a cell will respond in one of two ways: 1) rehabilitation, by attempting to repair the problem and move on, or, if the damage is unfixable, 2) death, through a programmed suicide called apoptosis. The ability to evade apoptosis, and thus continue to exist and multiply with damaged DNA is key to the development of malignancies and a hallmark of cancer.

So what does Socrates have to do with apoptosis? First of all it is not the fact that both of them are Greek (the word apoptosis comes from ancient Greek and means the ‘falling off’ or ‘dropping off’ of petals from flowers or leaves from trees). Through Crito’s dialogue with Socrates, Plato introduces the idea of social contract in western philosophy. Unjust as his condemnation might be, Socrates understands that, above individual urges, there are compromises to be made if we are to live collectively. So, like Socrates, our damaged cells will drink their hemlock (in their case, initiate a molecular cascade that culminates in self-digestion) and avoid risking the colony. One might say: “sure, but unlike Socrates who had the choice to leave, these renegade cells have nowhere else to go”. I’d say they would certainly escape if they could! In fact, some of them have and are living their deranged and immortal lives in media flasks all over the world (including at The Institute of Cancer Research).