The wobble of life
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You’re a unique human being – a combination of the genetic material from your parents, mixed together with the influence of the world around you, from the very first moments of your existence through to whatever you’re up to right now as you listen to this podcast.
Over the past century, the field of genetics has got the hang of the idea that it’s not nature OR nurture that shapes us, but nature AND nurture. But as we move into the next era of biology, it’s time to add something else to the mix. Let me explain.
We all start life as one single fertilised egg cell - a biological singularity created at one point in time, containing one human genome. That genome is copied, and each copy allocated into two new daughter cells, and we’re off.
One cell becomes two, two become four, four become eight, then sixteen, then thirty-two, and so on until there’s a little football of cells. And every human that ever lived started life as a tiny blob of stem cells inside a ball just like that.
As development unfolds, these cells continue to multiply, communicate and specialise. Some become head, others heart. Some are destined to be limbs, or liver, or lungs. And all the time, genes are being turned on and off, at the right time and in the right place to build a baby.
And it’s from here that we encounter one of the biggest mysteries of life: if all these cells have the same underlying set of genetic instructions, how do we make all the different tissues of the body.
Here’s where we meet the concept of ‘epigenetics’ – the science of how specific patterns of gene activity are established and maintained in different types of cells that all start with the same underlying genome. If you’re interested in learning more, go back and check out episode 15 of series 3 – Pimp my genome – about the wonderful world of epigenetics, including a fabulous story about some Mickey Mouse mice.
This epigenetic decision-making is the mechanism by which genes respond to cues from the environment, whether that’s molecular messages from the cells around them or elsewhere in the body, or signals from the outside world. To put it simply, it’s how nature and nurture interact.
A huge field of scientific enquiry has sprung up around epigenetics over the past few decades – in fact, it’s the field I did my PhD in (before it was cool). New tools and technologies have allowed researchers to map the ever-expanding lexicon of molecular markings in and around genes in unprecedented detail, known as histone modifications, showing how they correspond with patterns of gene activity.
Then there’s the whole world of non-coding RNA, fragments of genetic material that play important regulatory and structural roles in organising our DNA and activating or switching off genes. Gradually, we’re building a clearer picture of how all this information and all these signals come together to turn genes on or off, as well as starting to figure out what happens when this goes wrong during developmental problems or in disease.
So, you might be thinking we’ve pretty much got this whole nature/nurture thing figured out. But you’d be wrong.
The star of our story is the tiny nematode worm Caenorhabditis elegans, known as C. elegans for short (the name roughly translates as ‘nice rod’). Checking in at a millimetre long, these little wrigglers have become a popular lab animal all over the world due to their small size, low maintenance, and the fact you can just pop them in the freezer if you want to go away on holiday.
One of their most intriguing characteristics is the fact that every single worm grows in exactly the same way to exactly the same number of cells – a precise 1,031 for an adult male – with each cell popping into existence right on cue.
It’s no surprise that C. elegans was the first animal to have its genome completely sequenced, back in 1998, by researchers keen to understand how genes control this developmental clockwork. And how do scientists try and understand how genes work? By breaking them, of course.
In this particular story, the genetic vandals in question are Ben Lehner and his colleagues at the Centre for Genomic Regulation in Barcelona – a beautiful building perched on the Mediterranean seafront on the outskirts of the buzzing city, and one of the few scientific institutes that really makes me regret my choice to leave the lab.
It all started when Lehner got interested in the question: why are we different? On the surface, humans all look the same, as do mice, or frogs, or fruit flies. But there are plenty of individual differences. Even identical twins, who share the same DNA as the result of one fertilised egg or early embryo splitting in two, are not exactly the same.
But conventional wisdom can explain all of this either by invoking genetic alterations that randomly occur as we go through life, or the influence of the environment, wrought through epigenetic mechanisms. So, we have nature, and we have nurture. But then Lehner discovered something else.
It went like this. C. elegans worms growing in a lab are all effectively super-identical twins. They all share the same DNA and are grown in identical conditions so they all share the same environment. Same nature, same nurture. So, they should all respond in exactly the same way when one of their genes is broken, right? Right…?
When Lehner and his colleagues Olivia Casanueva and Alejandro Burga set about breaking a whole bunch of genes in worms, one at a time, they noticed something strange. For one gene, while 80% of the worms would be affected, 20% would be just fine. For a different broken gene, half the worms would be broken, the rest were just carrying on like nothing was wrong.
This isn’t down to random mutations elsewhere in the genome – they checked – and it can’t be down to differences in the environment as that’s tightly controlled. So that rules out nature, and it also rules out nurture. There must be something else. And that something else is what I like to call ‘The Wobble’.
What Lehner and his colleagues have revealed with their worm-breaking experiments is that the degree to which the effects of a genetic alteration, or mutation, are felt by an organism – known as penetrance – is influenced by subtle random variations in the activity of other genes.
Under normal circumstances, when all the genes are fully functional, this doesn’t matter. But start breaking the system a little bit – either by adding genetic mutations or by changing up the environment – and these subtle random differences start to have a bigger impact.
To explain why, we need to take a step back and think about what happens when a gene is activated. A large complex of molecules, collectively known as RNA polymerase, has to assemble on the DNA where the gene starts. Then this gene-reading machinery has to progress all the way along the gene, creating a kind of molecular photocopy out of RNA. It’s this RNA copy that then acts as the instructions that tell cells to make various proteins.
Switching genes on and off therefore isn’t like flicking a light switch on or off. It’s bit more of a flaky process. The RNA polymerase complex may take a long time to fully assemble, or it might fall off the gene before it’s finished reading. And some genes may be very active, cranking out hundreds of RNA copies per minute, while others may only make one or two. Some of this depends on the repertoire of transcription factors that are around, which are the proteins that help assemble RNA polymerase onto a particular gene. But there’s also a hefty dose of random chance.
The gene Lehner and his team have studied the most encodes one of these transcription factors. When it is mutated, half the worms die and half of them live – a fifty-fifty chance event. Then they looked at the activity levels of all the other genes in the worms that made it and the ones that didn’t, to see if these chance fluctuations in gene activity were to blame. They found that if activity levels of two other genes happened to be a bit higher than usual, there was a 90% chance that worm would survive. But if they were low, it was unlikely to make it.
The fact that enormous amounts of biological machinery have to be assembled in order to read a gene takes us from the realm of biology and into the world of physics. Wherever atoms and molecules are interacting on this scale, there’s the capacity for random shenanigans – more formally known as ‘stochasticity’.
Down at this level, there can be some pretty weird wobbliness, such as the ‘quantum jitters’ in the structure of RNA and DNA. Interactions that are conducive to gene-reading can also be encouraged by packing lots of the right molecules into the same place in the cell, but it’s still essentially a matter of chance. We have nature, we have nurture, and we have ‘the Wobble’.
As Lehner told me when I went to interview him while researching my first book, Herding Hemingway’s Cats, “It’s extremely complicated. There are molecules bombing into each other and moving around, and that’s the ultimate cause of all the stochastic things we see. It’s just a question of how far back we have to go.”
In the case of development, it’s all the way back to a single fertilised egg and those early, frenetic days of life. This is the most dangerous time in an organism’s life, as any tiny differences in gene activity, random genetic mutations or tiny environmental changes that occur here will be amplified throughout the body as it grows. In fact, it’s pretty amazing that anything makes it through the process alive. But rather than being a detriment, all these little sources of variation – nature, nurture and random ‘wobbles’ – act together to help make development robust, providing potential workarounds for anything that life throws at us.
Increasingly, it’s turning out that this wobble may be fundamentally important to life. It may even be responsible for determining which genes are on or off and which cells do what, depending on whether or not they randomly blip above a certain level of gene activity at a crucial point in development. And there’s also the potential for random wobbles in gene activity or environmental influences to reveal the negative health impacts of genetic mutations, leading to disease.
Despite its obvious importance and the exciting implications of the role of stochasticity in biological systems, by its very nature this stuff is incredibly hard to study. We’re talking about random fluctuations at individual genes in individual cells in individual organisms. And although to some extent stochasticity can be mathematically modelled and predicted on a relatively broad scale, it’s almost impossible to know exactly how the processes of life will play out in any single cell or individual.
This revelation helps to explain one of the things I found most frustrating back in the days when I worked in a lab trying to understand how various control switches in DNA affects the activity of nearby genes. Back in the days before CRISPR, when you had to do things the really hard way, my colleagues and I would spend months or even years trying to genetically engineer mice with missing or altered switches.
If we were very lucky, we’d get animals born that would have something wrong with them that mimicked humans with the same genetic problem, allowing us to probe further into what might be going wrong and potentially how to fix it. But more often than not we’d end up with mice that appeared to be totally normal. And it wasn’t just us – this is a common problem in genetic research, that knocking out a control switch, or even a whole gene, has no effect whatsoever.
However, these were lab mice, living in the murine equivalent of the lap of luxury – warm, well-fed and safe in the lab. As my colleague Rob would always say whenever we heard about a genetic alteration that apparently did nothing, “Ah, but did they take their mice to the moon?”
It’s a silly way of making an important point: while a genetic mutation might not matter under ideal lab conditions, it could become more important when the environment changes. Imagine you’re trying to figure out how a car works by using the same approach. If you take out the battery or siphon out the fuel, it won’t go at all. Cut the brake cable and you can start out just fine, but you’ll soon run into trouble the first time you need to slow down or stop. But cut the wire that powers the windshield heater and you might never notice an issue – until, of course, the first cold day. But if you live somewhere hot and sunny all the time, then it might never matter at all.
Luckily for us and everything else on the planet, life doesn’t work like a car. Although there are some genes that are absolutely essential, there are many that aren’t. The fact that biology is shaped by evolution, rather than design, makes it able to cope with a lot of genetic variations, mutations, environmental changes and general wobbliness around the edges. And, frankly, we need this wobbliness just to stay alive.
“There are errors in everything,” Lehner points out to me. “Errors in copying DNA, transcription and splicing; mistakes in translation; problems with protein folding; errors in protein modifications. Biology has to be able to deal with quite high percentages of stuff being wrong.”
There is a view that treats life in engineering terms, as if biological systems were somehow neatly and efficiently designed. But this simply isn’t true. Regardless of the protestations of believers in intelligent design – a position so intellectually contorted it belongs in a philosophical circus – nobody designed biology.
Living systems are a mess of redundancy and sometimes frankly ridiculous workarounds, which have evolved over aeons with the sole aim of keeping an organism alive long enough for it to pass its genes on to the next generation and start again. This story of the interplay between nature, nurture and the random wobble of life tells us we need to completely banish the idea that our genome is a fixed, deterministic blueprint that controls everything about who we are and how we work. Being alive and existing in our environment, with all its opportunities for random molecular shenanigans, is what constructs us, in all our wobbly, unique and mysterious glory. Enjoy it.
