One of the main things I’m dreading when our daughter starts nursery soon (aside from a phone call saying “your little one has bitten another child, you can collect her from the police station”) is the illnesses she will inevitably pick up. Ah well – coughs and colds and D&V are all part of life, aren’t they? Some people would call it ‘character building’! No. Those people are idiots.
But it is true that childhood infections do prepare our bodies for potential threats to come – and sometimes in surprising ways. Over decades of research, scientists have identified how picking up normal everyday illnesses could reduce chance of developing some rare but devastating conditions, including the most common form of childhood cancer, called acute lymphoblastic leukaemia, or ALL.
Acute lymphoblastic leukaemia affects around 250 kids under five every year in the UK, or about 6 in 100,000 children in this age group. It can be fatal if left untreated, but thankfully, due to decades of research, 9 in 10 patients are now able to be cured. However, the treatment for ALL is tough and can result in lifelong side effects, so it is still vitally important to understand how it can be prevented.
In May 2018, Professor Mel Greaves published a review of decades of research, his own and others’, setting out the most likely explanation for the causes of ALL. The development of the most common subtype of ALL (which involves a type of white blood cell called a B cell) involves two essential steps.
Step one – before birth
The first occurs before a child is even born. A blood cell acquires a particular fault in their DNA, which enables these cells to persist when they might normally die off – they are now “pre-leukaemia” cells.
We know this based upon several lines of evidence – one of which is the study of twin pairs, where one twin has leukaemia and the other one doesn’t. In twins which shared a placenta at birth, it has been shown that the healthy twin sometimes carries the same pre-leukaemia cells carried by the twin with leukaemia. The reason for this? It’s down to the shared placenta, which provides the opportunity for blood to be exchanged between the two twins in the womb. This means that pre-leukaemia cells from one twin get passed onto the other.
What causes this initial mutation? In absence of convincing evidence to prove otherwise, it’s most likely that this mutation is just a random event – one of the many hazards that can occur during development of a fertilised egg into a full grown baby.
Step two – infections causing havoc
The second set of mutations are what take the pre-leukaemia cells and turn them into full-blown cancer. How this ‘second hit’ occurs is where things get messy.
The pattern of mutations found in leukaemia cells have the tell-tale signs of being caused by molecules called RAGs. The normal role of RAGs is to edit a specific region of DNA in immune cells to match up random combinations of DNA segments, which provides the immune system with an almost infinite potential to respond to a wide range of threats.
RAGs aren’t normally active in the immature B cells, which form the most common subtype of ALL. However, RAGs may be inadvertently activated in these immature B cells during the process of an immune response, via a mediator called AID. And so the theory goes that in infections let RAGs loose in pre-leukaemia cells, causing genetic havoc and eventually leading to full-blown leukaemia.
What’s more, there’s plenty of evidence that backs up the idea that an unusual pattern of infections in early childhood have a role in the cause of ALL.
Day-care and leukaemia
One example of this evidence comes from examining the rate of leukaemia in children who attended day-care activities – nurseries, playgroups and so on. A major review of several independent studies published in 2010 demonstrated that infants who attended day-care activities had a lower risk of developing ALL than those who did not – about 25% lower. In these studies, regular attendance at nurseries and other day-care environments was being used as a measure of childhood infections, as this is where children pick up most of the common bugs they experience in early life.
Other evidence that backs up the idea that exposure to everyday bugs and illnesses can reduce risk of ALL include:
- Mode of delivery: children born by caesarean section rather than via the vagina – which houses a range of different microbes – may have an increased risk of leukaemia
- Breastfeeding: longer breastfeeding duration reduces risk of leukaemia in children – possibly due to the exposure of antibodies and some bacteria present in breastmilk
- Having older siblings: first born children have a higher risk of ALL than subsequent siblings
The idea connecting all these pieces is that the immune system has evolved to expect to be face multiple illnesses during childhood, and uses this as training for how to behave appropriately to potential threats in the future. But delaying this exposure to disease removes this basic training, and allows it to pick up bad habits and behave abnormally.
This idea, known as the “delayed infection” hypothesis, also explains the reason why childhood leukaemias are more common in developed nations than developing nations. Other conditions, such as Hodgkin Lymphoma, autoimmune diseases, and allergies, follow a similar pattern. In developed countries, we have become over time more concerned about hygiene, which of course is a good thing and prevents plenty of avoidable sickness. But the drawback might be that we’re not giving our immune systems the basic training that they’ve evolved to expect.
It’s really important to point out that parents are not to blame if their children develops leukaemia. There’s absolutely nothing that could have done to prevent the accidental mutation that occurred before birth, and less than 1% of those who carry those mutations go on to develop ALL.
So is acute lymphoblastic leukaemia preventable?
It is worth reiterating again that acute lymphoblastic leukaemia – and other types of childhood cancer – are thankfully very rare. But if we could do something to protect kids from these diseases, would it still be worth doing? Of course, it would be no more possible to send kids to mandatory nursery, than it would be to force mothers to breastfeed or to not have caesareans – regardless of what the reason was.
But identifying the situations, like nurseries, when the immune system is trained to behave itself, reveals a potential alternative route to preventing leukaemias. Could we distill the “training” that occurs in nurseries into some sort of vaccine, which can be offered to all children alongside their other routine immunisations?
It’s an intriguing possibility, but definitely a while off yet. One of the main hurdles of this approach is that it isn’t any specific bacteria or virus that is acts to train the immune system, but more of a bombardment by a variety of different bugs – some of which may not even cause any symptoms. How do you bottle the messiness of a nursery, or the hand-me-down illnesses from an older sibling, into a vaccine?
Prof Mel Greaves’ review of a lifetime of groundbreaking research points to the potential of potential for preventing ALL, and potentially other illnesses too. Personally, I find it fascinating that nurseries and playgroups could be benefiting children in more ways that we might imagine. When kids go to nurseries, to meet other children and learn new things, their immune systems are also doing some learning too of a very different kind.