Not quite in the beginning, but only a little bit after, a cell came to be amid the waters.

To glimpse it, we'd need to go back four billion years, to when the Earth was a world of water. The only breaks in the ocean were the tips of volcanoes, which belched the planet’s innards into its poisonous orange sky. Huge flaming asteroids fell as easily as raindrops.

And that was alright with Luca. Scientists call it Luca, or Last Universal Common Ancestor, because this cell was the source of everything alive today. Though Luca itself is long gone, its genetic code, the instructions that allowed it to survive and thrive in a boiling world without oxygen, can still be read in the much more complicated manual that sits in the centre of every cell of your body, and every cell on Earth.

Luca is the pivotal character in the story of life; the single seed that flowered into dinosaurs, roses, mole-rats and E. coli – our entire supportive, squabbling family tree.

But the story of life, like all the stories told by Luca’s children, has two sides.

In this article, we're exploring how evolution is shaping the future of cancer research. It's a companion piece to our takeover episode of The Rest Is Science, the podcast where curiosity meets discovery. You can use the menu at the top of the page to jump straight to different discoveries and research projects, or scroll to the end to watch the full episode.

Luca was one lone cell. Before it could rule the world, it would need to reproduce. You're reading this because it did, by copying its full genetic code (its genome) and dividing in two.

That’s hard to do without making mistakes, but Luca was lucky: its mistakes allowed it to evolve. Today, Luca’s legacy is built from all the things it got wrong.

Small, random copying errors led to genetic changes, or mutations, that took Luca’s various descendants down different developmental paths. Some of those mutations helped cells survive and succeed in their changing world, and then some of these cells adapted to work and evolve together. A few eventually fused or grew into complex multicellular beings.

At that point, evolution gained a new layer.

Multicellular organisms evolve as a whole, but they’re still made up of individual cells that replicate like Luca. That’s a dangerous tension. It means a single cell dividing inside a larger body can pick up mutations that make it compete with the cells it’s supposed to be working alongside.

If the body can’t stop it, that cell will start an evolutionary process of its own. We call that process cancer.

In many ways, cancer is evolution; it's the power that shaped billions of years of life running amok inside one living body, fast enough for us to see it. Treating cancer is so complicated because it means pushing back against the force that led any of us to exist at all.

But pushing back doesn’t have to be the only option. With Cancer Research UK’s support, scientists in the UK and beyond are reclaiming evolution's power, turning cancer's biggest advantage into a weakness it can't escape.

This is the next stage in Luca's story. Read on to find out where it might lead.

The forest and the trees

Luca’s story shows how an entire ecosystem can sprout from a single cell. In the same way, tumours might start with one change, but they're unlikely to be balls of identical copies – they're more commonly like forests, full of different species.

That diversity creates resilience. A fire or a drought could destroy most of a forest, but some plants and seeds will probably have adaptations that help them survive. Then, when there’s nothing else left for them to compete with, they’ll grow back, forming a new ecosystem that can better withstand the conditions that almost wiped out the last one.

Lung cancers are some of the world’s most complex forests. No two are alike, and each can grow to include billions of different cells. Treatments are likely to kill most of them, but some may have picked up mutations that help them hold out and grow back.

In 2014, TRACERx, the world’s largest lung cancer study, set out to map how this happens and identify the best ways to stop it.

TRACERx, which was led by Cancer Research UK's former chief clinician, Professor Charles Swanton, stands for Tracking Cancer Evolution through Treatment (Rx). To make it work, Swanton and his colleagues needed to collect samples from hundreds of lung cancer patients and record the patterns of DNA changes in different parts of their tumours at different points in time.

By the time they'd done that, the team had analysed as many 'letters' of genetic data as would fit in 50 million copies of the complete works of Shakespeare. They used that data to grow a new forest of evolutionary trees, revealing the ways a cancer’s past could determine its future.

A journey through time

With their new understanding of how lung cancers can evolve, the TRACERx team were able to create tools like blood tests to help doctors predict what’s coming and stay one step ahead.

But that was only part one. As their work took them further back into lung cancer’s past, the researchers got closer and closer to cancer’s equivalent of Luca – the universal, or ‘truncal’, mutations that appear just as the evolutionary tree is forming and are replicated in every branch.

Identifying these changes gives us a much clearer idea of how to stop cancer for good. Cancers can adapt to resist treatments that prune the outer branches of their evolutionary tree, but drugs designed to chop through the mutations in the trunk can bring the whole thing down.

That's if the tree can start growing at all.

TRACERx also linked truncal mutations in early lung cancer cells to specific changes in the cells' appearance. These changes are cancer’s earliest warning signs: tiny red flags that can alert the body’s defences (the immune system) to approaching danger. By following evolution's path backwards, TRACERx was even able to spot them on cells that weren't yet cancerous.

That discovery led directly to LungVax, the world’s first vaccine designed to prevent lung cancer in people at high risk. It uses COVID-19 vaccine technology to show the immune system how to recognise the signs of lung precancer, so cells can be removed before they cause problems.

LungVax will be tested in people for the first time later this year. If the early results match the promise already seen in the lab, it could mark the beginning of a new era in preventing cancer.

Rewriting the rules

TRACERx’s smooth evolutionary trees are the descendants of the ones Charles Darwin sketched into his notebook when he was first developing his theory of natural selection.

Back then, when the wrong kind of science could cost you your reputation, Darwin tended to work by himself. But today there are scientific questions that no one researcher, institution or even country can answer alone. Cancer Grand Challenges, which Cancer Research UK co-founded with the National Cancer Institute in the US, is our way of bringing those kinds of questions – the ones that might reframe everything we thought we knew – to the boundary-crossing teams that can answer them.

One of those teams is eDyNAmiC. Its members approach evolution in the same way they might play jazz.

That's all about encouraging eDyNAmiC's researchers to think creatively, but it’s also a good way to explain the phenomenon they’re thinking about. The team’s insight is that, although cancer exploits evolution, it doesn’t always follow the rules.

Take, for example, glioblastoma, one of the fastest-growing and hardest-to-treat types of brain tumour. In some cases, these cancers can adapt to resist effective targeted treatments within a week. That kind of evolution, with mother cells spawning daughters that look like they come from completely different species, is more like a tangled bush than a branching tree.

Scientists spent years observing this kind of chaotic behaviour in tumours – sudden growth spurts, unexplained drug resistance – without understanding how it could possibly happen. Then, in a moment that set the stage for the grand challenge, eDyNAmiC’s researchers spotted what everyone else had been missing. 

How to trap a cancer

Multicellular organisms usually keep their genomes neatly coiled into molecules called chromosomes in the centre of each cell. These tight structures ensure cells stay stable when they divide, so skin keeps acting like skin, lungs do the job of lungs, and mutations can't happen too quickly.

But other forms of life don’t need things to be so coordinated. Bacteria toss frisbees of extra DNA called plasmids all about their cells, effectively turning every cell division into an evolutionary experiment.

Team eDyNAmiC’s researchers found that many of the hardest-to-treat cancers can use the same trick. Mutated cancer-driving genes can break loose from their restrictions and form rogue circles of extrachromosomal DNA (ecDNA).  

Unlike chromosomal DNA, ecDNA isn’t split equally every time a cell copies its DNA and divides. That means closely related cells can begin to look very different, very quickly. Even truncal mutations on ecDNA can wax and wane in different parts of a tumour from one generation to the next, making them much harder to target with traditional drugs. 

But living on the edge like that is dangerous. To survive, ecDNA has to keep outrunning the chaos it creates, and eDyNAmiC's researchers have identified a way to exploit that vulnerability.

Stanford University Professor Howard Chang, who played a key role in the research, likened the approach to judo.

“Rather than just trying to hit the cancer cells as hard as we can, this strategy is trying to use their own excess, their own momentum against them.”

Chang and the team used a targeted drug to block the only safeguard that protects ecDNA from its own mess. In lab tests, the treatment directly shrank stomach cancers and stopped them from adapting to resist another effective cancer drug.

Around 1 in 6 cancers evolve using ecDNA. They're often the ones with the worst outcomes. The team hope the drug they identified, which is being tested in clinical trials by the company Boundless Bio, will make a real difference for the people whose cancers are currently hardest to treat.

Another Cancer Grand Challenges team, REWIRE-CAN, is also investigating ways of turning cancer’s behaviours into vulnerabilities. The team is developing drugs to hyperactivate bowel cancer cells, putting them under so much stress that they shut down or self-destruct.

Extrachromosomal DNA is evolution at its wildest. But the billions of years of slow and steady change that brought you to this moment have left other strange legacies. Your cells are haunted by their past, and the ghosts they hold can come back to life. 

There are less creepy ways of putting that. Using the common metaphor, we can say that only 2% of a person’s full DNA instruction manual (the genome) includes straightforward instructions. The other 98% does something different, in a way scientists don’t entirely understand. 

At first, they thought this ‘dark genome’ was all junk left behind by evolution – and some of it does seem to be useless. Other sections interact with the instructions in the light genome, but as if they were written in a slightly different language. The weirdest bits are DNA remnants of other things entirely, including viruses that infected our predecessors millions of years ago and then, unexpectedly, helped make us who we are.

That's not an exaggeration. If not for the ghosts of ancient infections, humans might hatch from eggs.

The reason we don't is the placenta, which develops during pregnancy and combines genes from the mother and the foetus. The light genome doesn't have the tools to build something like that, but viruses make their living by melding with other things. Scientists think the placenta came about thanks to repurposed ‘dark’ genes that viruses had previously used to bind with and enter our ancestors’ cells.

Other elements of the dark genome, so-called ‘jumping genes’ (or transposons), which flit about and modify different genetic instructions as species evolve, seem to have taken away our tails. A similar quirk might explain why we like the taste of bread. Some ancient viruses even left instructions to help our immune systems fight off future infections.

As Professor George Kassiotis, a leading dark genome researcher at the Francis Crick Institute in London, puts it, the viral DNA in the dark genome is "a very powerful force” for evolution. Unfortunately, that means cancers can use it “for their own evolution inside one human body”.

Kassiotis is working with the TRACERx team to uncover just how the dark genome can influence tumour growth. So far, he’s found that cancer cells can also reach back through time and reactivate instructions from ancient viruses. At times, it's as if they can disguise themselves in the same cloaks that helped old infections get past the body’s defences millions of years earlier.

But not every cloak is a good disguise. Another researcher at the Crick, Professor Samra Turajlic, has found clues that suggest activity in the dark genome could make kidney cancers especially vulnerable to immunotherapy.

Turajlic, the new head of the Cancer Research UK Manchester Institute, first noticed this possibility before she began to look at the dark genome directly. That suggests we'll learn a lot more as we turn on the lights in the years to come. Far from being a rubbish bin, the dark genome could be full of keys to better cancer treatments.

TRACERx EVO is already exploring how the dark genome contributes to lung cancer evolution, and another new Cancer Grand Challenges team, ILLUMINE, is just beginning a comprehensive search for ways it might expose other hard-to-treat cancers.

Because life is so interconnected, clues about the ways our cells work can hide in the most unexpected places.

The side-blotched lizards of California’s Mojave Desert look different depending on where you find them. If you spook one that lives in the sands towards the black slopes of the Pisgah volcano, you might see its skin darken. 

If that same lizard went back down into the dust, the colour change would reverse, as it would for a chameleon. But something much stranger would happen if it stayed put. When one of these lizards settles on the volcano’s hardened lava flow, its darkened skin begins to wrap itself into its offspring’s DNA.

Mutations haven’t driven this change so much as signed it off. From a Darwinian perspective, that’s backwards. 

But it got Dr Alejandra Bruna, from the Institute of Cancer Research in London, thinking. She studies cancer in children and young people, which can seem backwards, too. These cancers are rarely driven by genetic changes that build up in our cells over time, because there's been so little time for those changes to happen. They're diseases of development, rather than ageing, and developing cells have other ways to adapt.

For Bruna, the lizards were a missing link.

Children’s and young people's cancers often begin in cells that are rapidly diversifying to build all the various parts of a complicated human body. To do that, they need the lizard-like ability to start directing their evolution without changing their genetic code.

So, unlike the lung cancers tracked by TRACERx, cancers in children and young people don’t necessarily need a diverse ecosystem to resist treatment. Instead, they can rely on cells that rapidly change their appearance (their phenotype) to help them adapt to their surroundings. At times, like cells with ecDNA, those cells can even play dead.

Now they've identified that behaviour, Bruna's team are working out ways to stop it. They're using tiny, purpose-built recorders to monitor how children's and young people's cancer cells adapt, so they can spot any signs of shape-shifting and choose specific treatments to stop them coming back.

"Oncology research has long focused on what changes in the genome," Bruna explained on Cancer News last year. "We are now realising that the answers to relapse may lie in what does not."

When you trace life back to Luca, you can’t help but notice its contradictions. Evolution exposed us to cancer, but it also gave us the brains and ingenuity to stop it. 

It hasn’t left us to work on the problem alone, either. For as long as cancer has existed, there's been pressure on animals to prevent it. If evolution hadn't led to special ways of stopping cancer, some animals would live much shorter lives, and huge ones like elephants and whales might not be able to exist at all.

To put that in research terms, it’s like evolution has spent millions of years running a global cancer prevention trial. Now, finally, we have the tools to read the results.

The big realisation is that different animals have uncovered different cancer-preventing strategies. Each one is a potential angle for humans to explore.

Elephants, for example, carry extra copies of tumour-suppressing genes. So, though they have many more cells that could turn cancerous, they also have many more ways to stop potentially dangerous changes before they cause problems.

At the other end of the size scale, long-lived naked mole-rats seem almost entirely immune to cancer, possibly because they can squash potential cancer cells by pressuring them from outside. And some bats, which have to cope with the extra strain of propelling themselves through the air, have developed remarkable ways of reversing ageing and repairing DNA damage.

None of this means scientists will be turning animal cells into cancer treatments anytime soon. Evolution has made us different, and there's still more work to do (from isolating cells with microscopic lasers to counting the rings in whales' earwax) to confirm exactly which adaptations are the most important. What we can say today is that there are more effective ways to stop cancer out there. Studying animals could help researchers bring them to people sooner.

The answers within

Then again, not everyone needs extra support.

We’ve all heard stories of people who, despite a lifetime of smoking, drinking and facing exposures that should increase their risk of cancer, somehow manage to avoid the disease. There’s no way of knowing who those people will be beforehand, but luck isn't the only explanation. A small but extraordinary group of humans seem to have a natural resistance to cancer.

It's as if some of us have been sorted into a more successful part of evolution's cancer prevention trial. To really learn from it, researchers need to find what's being tested - the thing that sets "super-avoiders" apart.

Cancer Grand Challenges team ATLAS has an idea about where to look.

All through your life, your immune system has been writing its own version of your story. It picks things up after the genome's prologue - the evolutionary tale of how your cells came to be - and puts all the attention on the things you've faced since you got here.

To be clear, this probably isn't an autobiography you'd want to publish. It's more rhinovirus (the cause of the common cold) than romance, and it's written in your blood. To ATLAS, though, the information it contains is priceless.

That's because whenever the immune system notices a new intruder or threat, it creates a targeting protein, or antibody, to lead an attack against it. Antibodies may not always be up to the job of stopping an infection or removing a potential cancer cell, but they stick around in your blood throughout your life, just in case they're ever needed again.

For a researcher like Dr Paul Bastard, ATLAS's team lead, these antibodies are a bit like the immune system's chapters. Each one explains a little bit more about how your body's defences have evolved. If you're a super-avoider, some of them could contain your cancer-preventing secrets.

With Cancer Grand Challenges funding, ATLAS's researchers are setting out to read the stories in the blood of more than 60,000 people to work out exactly what sets super-avoiders apart.

They're particularly interested in a subset of antibodies called "autoantibodies", which can target the body's own cells. When it comes to cancer, autoantibodies can either help the immune system remove dangerous changes early or block immune cells from responding when they should.

So, there are two sides to the immune system's story, too. The more we understand it, the more we can do to tip the balance. ATLAS's plan could uncover the best tools ever developed for protecting people against cancer. And, one day, it could be possible to replace harmful autoantibodies with helpful ones.

Cancer started when evolution turned on itself. Now, scientists are revolutionising cancer research by turning it just a little bit further.

Instead of reacting and pushing back after cancer evolves, these projects are using our understanding of evolution to get one step ahead. They're also creating opportunities for us to channel evolution into new ways to overcome cancer - using the momentum that brought us all here to help us stay healthy, and together, for longer.

That's the power of going back to the beginning. If there weren't two sides to this story, we wouldn't be able to change it.

Over the past 50 years, our pioneering work has helped double cancer survival in the UK. Our partnership with The Rest Is Science is highlighting the groundbreaking discoveries behind that progress and the ways research is evolving to achieve even more.

To hear more about how Cancer Research UK scientists are turning evolution’s tricks against cancer, you can listen to our special takeover episode: