This entry is part 8 of 30 in the series Our milestones
In this next post in Our Milestones series, we look at a rather surprising discovery made by Professor Gerard Evan and his team at the Cancer Research UK London Research Institute in the early 1990s.Their results overturned established thinking, leading to a massive leap in our understanding of the intricate mechanisms that drive cancer and ultimately paving the way for new treatments.
It all centres on a gene called Myc, which was known to be an “accelerator” gene (oncogene), responsible for driving the growth of cancer cells. But Professor Evan and his colleagues showed that Myc could also cause cancer cells to die – the complete opposite of what was expected. The scientists published their findings in the journal Cell in 1992, shaking up the whole field of cancer research in the process.
Let’s look in a bit more detail about how the team revealed Myc as both a bringer of cell life and cell death, and why it was so important.
A bit about Myc
Our story starts back in 1981, with a paper published in the journal Nature from researchers studying avian leukosis virus (ALV), which causes lymphoma in chickens.
The researchers discovered that cancer starts when the virus DNA smuggles itself into the DNA of a chicken cell, nestling next to the Myc gene. And when the virus DNA switches itself on to make more viruses, it accidentally switches Myc on too.
Because (as we’ll see later) Myc is a gene that normally tells cells to divide at the appropriate time and place, this unexpected ‘switching on’ of Myc makes the chicken cells multiply out of control and form tumours. The results revealed that Myc is an oncogene – a gene that’s normally involved in cell division, but can drive cancer if it’s switched on inappropriately.
Over the next decade, scientists around the world got to grips with Myc, trying to understand what it did and whether it was involved in human cancers.
In 1991, researchers in the US showed that the Myc gene makes a protein called a transcription factor – a type of molecular ‘switch’ that can turn specific genes on and off. This led researchers to suspect that Myc must be switching on yet more genes that tell cells to divide, although the identity of these genes wasn’t known at the time.
More evidence joined the growing pile. Abnormally high levels of Myc were found in a range of different tumours, strongly hinting at a role in human cancer. Tests on cells grown in the lab showed that cells produce high levels of Myc just before they divide. And when cells go into a ‘resting’, non-dividing state, they switch off Myc production.
The case seemed watertight – Myc was there when cells divided, it wasn’t there when they weren’t, and it probably caused cancer if it was switched on inappropriately. But the unexpected results Evan and his team found turned this idea on its head.
Lured to London
Dr Gerard Evan (as he was then) first became fascinated by Myc in the 1980s, when he was working on oncogenes in Professor Mike Bishop’s lab in sunny California. Lured back to Britain – by opportunities for interesting science rather than our weather – he joined the London Research Institute in 1988, focusing on trying to find out what Myc was up to in cancer cells.
To find out, Evan and his team studied rat cells grown in plastic dishes filled with nutrient ‘soup’, which had been genetically engineered to carry a version of the Myc gene that was constantly switched on. As might be expected, the cells multiplied rapidly under normal conditions. But something very odd happened when the conditions changed.
An important component of the cells’ nutrient soup is serum – a rich liquid packed full of proteins and other useful chemicals that encourages cells to grow. Without it, cells stop dividing and go into a resting state.
The researchers noticed that when they reduced the amount of serum in the broth, the plastic dishes that should have become packed with growing cells looked surprisingly empty. This was unexpected, because the constant presence of Myc should have kept them dividing happily, filling up the dishes.
When the researchers looked more closely they noticed something weird was going on. It wasn’t that the cells had just stopped growing – they were dying.
A deadly result
To find out what was going on, Evan turned to time-lapse video microscopy – a new technique that was just starting to be used at the London Research Institute. By recording images of the dying cells over many hours, the scientists discovered that they were ‘committing suicide’ through a process of controlled cell death known as apoptosis.
Every single day, millions of cells in our bodies undergo this process, neatly ridding the body of damaged and worn-out cells. Apoptosis also plays a vital role as we develop in the womb, for example by sculpting the spaces between our fingers and toes.
But when it comes to cancer, apoptosis is the flip side of cell growth. Although oncogenes drive cells to multiply out of control, tumours can only grow if the cancer cells don’t die. So as well as switching on genes that make them grow, cancer cells also have to shut down apoptosis so they can survive.
Interestingly, other scientists working on Myc had noticed this phenomenon in their experiments, but dismissed it as a quirk, figuring that the lab-grown cells were dying because they were “sick of Myc”.
Not so sick of Myc
Evan and his team weren’t so quick to ignore their discovery and dug a bit deeper. Further experiments proved that high levels of Myc were definitely responsible for the cell death they were seeing.
The researchers were intrigued. How on earth was Myc managing to do two contradictory jobs – making cells grow, but also making them die?
The team wondered if the answer lay in the 3-dimensional shape of the protein, because Myc isn’t just a blob – it has a number of distinct regions within it. So the researchers tested different parts of Myc in order to find out which bits gave life to cells and which brought death. This led to a second unexpected result – the regions of the protein responsible for driving cell growth were the same ones that drove cell death.
So what was going on?
Tipping the balance
The results from Professor Evan’s lab showed that the situation was much more complicated than anyone had previously thought. Not only could a single protein drive tumour growth, it could also – paradoxically – unleash death on cancer cells.
Evan’s work showed that cancer cells exist in a delicate balance of life and death, depending on the conditions they’re growing in. Because the same gene promotes cell growth and causes cell death, just a small push in one direction or the other tips the balance.
It also helps to explain why cancer isn’t even more common than it is. Although more than one in three of us will get the disease at some point in our lifetime, cells in our bodies are continually going rogue and multiplying out of control. If all of these developed into cancer, none of us would stand a chance. But Evan’s work shows that just a tiny change can trigger apoptosis, stopping a developing tumour in its tracks.
However, this safety mechanism isn’t perfect, as it relies on a cell having a fully functional molecular ‘suicide kit’ – a complex arrangement of genes and proteins that control apoptosis. If any of the components of this kit are faulty then the cell can’t die. Instead, it multiplies unchecked, leading to cancer.
Turning discoveries into treatments
In 2002, Professor Evan, as he was by now, and his team carried out experiments showing that combination of overactive Myc along with an overactive version of a gene involved in apoptosis (called Bcl) quickly led to pancreatic cancer. Importantly, switching off Myc made the tumours shrink. And in 2008 the team used a more sophisticated method to switch off Myc in lung cancer cells in mice, halting the disease.
These discoveries suggest that developing drugs to block Myc could lead to potent new treatments for cancer. And because Myc is faulty in so many different cancers, these could have a wide range of applications.
But there’s a slight catch – Myc is a tricky molecule to design drugs against, partly due to its shape and the way it works. It’s also involved in a multitude of processes inside cells, so it’s going to be tricky to work out exactly how to hit the ‘bad’ pathways that drive cancer, and switch on the ‘good’ pathways that could make cancer cells die.
Professor Evan went back to California in 1999, returning a decade later to head the Biochemistry Department at Cambridge University where his work is currently funded by Cancer Research UK. In 2004, he was recognised for his contribution to cancer research by being elected a Fellow of the Royal Society, a prestigious group of the world’s elite scientists.
More importantly, the work he carried out in the 90s is now beginning to bear fruit. Scientists and pharmaceutical companies around the world are now racing to develop Myc-blocking therapies, including Professor Evan and his colleagues, though they are yet to be tested in clinical trials.
The last two years has seen a whole host of new drugs appearing on the scene, built on the work of visionary scientists in the 1980s and 90s. As we’ve said elsewhere, we’re on the cusp of a new era in cancer treatment, based on our understanding of genes like Myc.
And every step provides more hope that these new treatments will end up saving many in the future.
Evan GI et al (1992). Induction of apoptosis in fibroblasts by c-myc protein. Cell, 69 (1), 119-28 PMID: 1555236
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