The forest and the trees

Luca’s story shows how an entire ecosystem can sprout from a single cell. In the same way, a tumour might start with one change, but it's unlikely to become a ball of identical copies – it's more like a forest, 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 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. As powerful and refined as today's cancer treatments are, that level of complexity means many tumours will still be able to adapt and survive.

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 outgoing chief clinician, Professor Charles Swanton, stands for Tracking Cancer Evolution through Treatment (Rx). To live up to the name, Swanton and his colleagues collected samples from hundreds of lung cancer patients and recorded the patterns of DNA changes in different parts of their tumours at different points in time.

By the time they were done, the team had analysed as many 'letters' of genetic data as would fit in 50 million copies of the complete works of Shakespeare. All of it helped them grow their own forest of evolutionary trees, revealing the ways a cancer’s past could determine its future.

A journey through time

Once they had laid out lung cancer's evolutionary playbook, 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 TRACERx team 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.

The treatments lung cancers resist are usually the ones that prune the outer branches of the evolutionary tree, creating space for other, better-adapted cancer cells to grow in their place. By contrast, drugs that can chop through the mutations in the tree's trunk can bring the whole thing down.

And if we know the mutations that appear in the tree's trunk, we may be able to stop it growing at all.

The TRACERx team didn’t just find truncal mutations in lung cancer cells. They also linked them to specific changes on the cells' surface. These changes are cancer’s earliest warning signs: red flags that can alert the body’s defences (the immune system) to approaching danger, and they start to appear before a cell turns 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 red flag signs of pre-cancer cells in the lung, so they can be removed before they cause problems.

LungVax will be tested in a small group of people with a high risk of lung cancer for the first time later this year. If the early results match the promise already seen in the lab, it could be possible to prevent people ever experiencing a cancer diagnosis, or cancer treatment, at all.

Meanwhile, TRACERx's successor project, TRACERx EVO, is taking an even more expansive approach to lung cancer. And TRACERx's evolutionary trees are providing a framework for researchers to interrogate other cancer types, too.

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 developed his theory 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 questions is why cancer doesn’t always follow Darwin's pattern.

The team answering it is eDyNAmiC, which approaches evolution in the same way it might play jazz.

That approach is 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 human evolution, it doesn’t always follow its rules. It’s like a cover version, with teasing traces of the original tune mixed up and syncopated until they’re unpredictable and strange.

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 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 only happen in small increments. 

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. Now, eDyNAmiC and a company called Boundless Bio have developed a drug to exploit that vulnerability. 

Stanford University Professor Howard Chang, one of the researchers on the team, likens the approach to judo.

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

The team's drug takes away the only safeguard that protects ecDNA from its mess. In lab tests, it 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 their new treatment, which is now in early-phase clinical trials, will make a real difference for the people who's 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 they seem to be written in a slightly different language. The weirdest bits are DNA remnants of other things entirely, like 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 ancient infections, humans might hatch from eggs or grow up in pouches like kangaroos. The reason we don't is the placenta, which has the unique ability to combine 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. However, 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 reactivate instructions from ancient viruses to help them get nutrients, grow and spread. it's as if they can put on the same dark cloaks that helped old infections get past the body’s defences.

But not every cloak is a good disguise. Another researcher at the Crick, Professor Samra Turajlic, is investigating whether activity in the dark genome explains why kidney cancers are more vulnerable to immunotherapy than many other cancer types.

Over the coming years, the dark genome will get much brighter. TRACERx EVO is already exploring its role in lung cancer evolution, and the new Cancer Grand Challenges team ILLUMINE is beginning a comprehensive search for ways it might expose other hard-to-treat cancers.

Far from being a rubbish bin, the dark genome could be full of keys to better cancer treatments.

Evolution turned upside-down

Because life is so interconnected, clues about the ways our cells work can emerge 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. 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 switch identity before changing their genetic code.

So, unlike the lung cancers tracked by TRACERx, cancers in children and young 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 hide in their surroundings. At times, like 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 they're shape-shifting and personalise treatment 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 all animals to prevent it. If they didn’t have special ways of stopping cancer, some 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 one is that different animals have uncovered different cancer-stopping strategies, which gives humans lots of potential angles to explore.

Elephants’ ability to avoid cancer could be linked to the fact their cells carry extra copies of tumour-suppressing genes, which gives them many more ways to stop potentially dangerous changes before they cause problems.

At the other end of the size scale, naked mole-rats, which can live 10 times longer than other tiny animals, seem to 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 special ways of repairing DNA damage.

None of this means scientists will be turning elephant cells into cancer treatments anytime soon. There's also 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 do know is that these animals are onto something. As soon as they're sure of the most suitable strategies, researchers can get to work applying them to treating and preventing cancer in humans.

The answers inside

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 their health isn't just down to luck. Evolution seems to have given a small but extraordinary group of humans a natural immunity to cancer.

These people are the focus of an ambitious project from Cancer Grand Challenges team ATLAS. As well as studying cancer's relationship with the immune system, Dr Paul Bastard and his team are following evolution away from the disease. They're exploring the immune systems of cancer “super-avoiders” to find new ways to protect everyone.

ATLAS is one of the points where evolution's cancer prevention trial most closely aligns with our own efforts to stop the disease. Science has made incredible progress by pushing back against cancer's evolution, but now the balance is shifting. This new generation of evolution-focused research is helping scientists capitalise on billions of years of our own evolutionary momentum. Already, we're learning that many of the answers we're looking for could be very close at hand - sometimes in bacteria, and sometimes in trees.

Similarly, immunotherapies and cancer vaccines work because of what's already in us. And with almost all the genome still dark, there's much more that researchers can do to keep improving them.

It only took one cell to create all this life. That doesn't mean one cell should be able to take it away.