Reading the code: Professor Tony Kouzarides

It’s been a busy month for Professor Tony Kouzarides. Not only has he been awarded one of our prestigious Gibb Fellowships, but he’s also been to Germany to collect the high-profile Heinrich Wieland prize, given to scientists who have made a significant long-term contribution to fundamental biological research.

We’re proud to have supported Tony’s work for more than 20 years at the Gurdon Institute in Cambridge. Over this time he’s made a number of significant contributions to our understanding of one of the most fundamental biological questions: how do genes get switched on and off?

His research work is helping to shed light on how this happens in normal cells and how it goes wrong as cancer develops, and has led to new treatments for cancer patients that are being tested in clinical trials. But, as we found out when we went to meet him, there are still plenty of mysteries to be solved.

From one island to another

As a young child growing up under the hot sun on the island of Cyprus, Tony wanted to be an archaeologist. What drove him then – as it still does now – is the thrill of discovering something new for the very first time, which nobody else knows.

He was 15 when war drove his family as refugees to the UK, and he describes being thrown into a new school in a foreign country as a “baptism by fire”. But he settled well enough to get to university, studying genetics at Leeds. And from there, he made his first foray to Cambridge as a PhD student, studying viruses in the Pathology Department with Professor Tony Minson.

“I was studying a virus that we thought might cause cancer,” Tony explains. “It turned out to be pretty feeble at causing cancer, but it got me interested in cancer genes.” The early 1980s, when Tony was starting out in research, was an exciting time for cancer scientists. They were just beginning to discover the first genes involved in driving the disease, known as oncogenes.

But rather than immediately getting stuck into studying specific cancer genes, Tony went to work with Bart Barrell at the MRC Laboratory of Molecular Biology in Cambridge. The scientists there were just starting to explore the data being generated by a relatively new technology – DNA sequencing, which enabled researchers to ‘read’ the molecular ‘letters’ that make up the DNA code.

The idea was that by lining up DNA sequences from different genes – even from different species – it would be possible to spot patterns and similarities that could reveal how they worked and what jobs they might do.

Tony says: “It was a time when we were asking the fundamental question ‘what is a gene and how does it work?’, and I was really interested in transcription – how genes get switched on and off. And I wanted to know how this worked in cancer.”

Spotting similarities

Pursuing this combined interest in cancer genes and the underlying patterns within them took Tony to New York, to work with Ed Ziff. Here, he focused on a new gene called FOS, which was thought to be somehow involved in driving cancer, although exactly what it did was a mystery. To find out more, Tony made the switch from studying DNA to protein.

Proteins are the molecules produced by cells from the ‘recipes’ encoded in our genes, and they’re made up of tiny biological ‘building blocks’ called amino acids. They’re put together in a precise order, or sequence, which gives the protein its shape and function.

Tony started lining up protein sequences produced by FOS and other oncogenes, searching for any similarities. He noticed that there was a sequence that was similar between a few of them, but it was pretty weak likeness – just a recurring pattern of a run of five of the same amino acid building block (a molecule called leucine). But what was it doing?

It took two years for him to prove that these repeated leucine blocks were important for helping FOS to stick to a protein made by another oncogene called JUN. His findings provided solid evidence that FOS and JUN could work together to turn on genes. We now know that they play an important role in driving cells to multiply, both in healthy cells where growth is tightly controlled, and in cancer where cells run amok.

Running the risk

“Pursuing my ideas about FOS was risky,” says Tony, “As many people didn’t believe that such a weak similarity could be important. If I hadn’t got the results I did, my scientific career would have been over. But I’ve always believed it’s important to take risks in my research rather than play it safe, and it’s something I still do now.”

The gamble paid off. Shortly after publishing his results he received a phone call from a scientist named Ron Laskey. Ron had secured funding from The Cancer Research Campaign (a precursor of Cancer Research UK) and the Wellcome Trust to set up a new research institute in Cambridge, bringing together top cancer researchers with the best people working in developmental biology. Would Tony like to come back to the UK and set up a lab in the new building?

Tony recalls:  “Ron had put together some amazing people. He came over to New York and we walked around Central Park talking about it. Coming back to Cambridge had seemed like an impossible dream, but he offered me the best job I could imagine.”

As a result, Tony became one of the first members of the new institute – in fact, the first two people he hired, Andy Bannister and Alistair Cook, are still with him today. Now known as the Gurdon Institute, it’s still funded by Cancer Research UK and the Wellcome Trust, and boasts two Nobel prizewinners – John Gurdon himself, and Martin Evans.

From cancer genes to epigenetics

Originally brought in by Ron Laskey to work on cancer genes and how they get switched on and off, Tony’s focus started to shift towards more fundamental questions about the mechanisms by which all our genes are controlled.

An important breakthrough came in 1996, when Andy Bannister in his lab made an intriguing discovery. A protein called CBP appeared to be able to stick little chemical ‘tags’, called acetylation, onto the histone proteins that package DNA. It may not seem like much of a big deal, but it changed everything.

Tony told us: “We already knew that CBP was involved in turning genes on, and we already knew that histones carried acetylation tags, but nobody had made the link between the two. Our work showed that CBP turned genes on by acetylating histones, and that this was a fundamental principle underpinning gene activation.”

The discovery, along with the findings that other researchers around the world were making, ignited the field of molecular epigenetics – the tags and markers on our DNA and the proteins that package it, which make sure that genes are switched on and off at the right time and in the right place.

But how does it work?

Since their first major result in histone acetylation, Tony and his team have gone on to discover other types of tags that help to control gene activity, dubbed by some as the “histone code”. But it wasn’t enough just to catalogue the different marks – he wanted to understand what they do.

Another crucial step forward came in the late 1990s, when they discovered that there were specific proteins that recognise and stick to a type of histone tag called methylation, which is added to the histones that package genes needing to be switched off.

The discovery was truly exciting, as it provided an explanation for how these chemical marks get interpreted by the cell and influence gene activity. And it also had implications for cancer, as Tony explains: “When Andy found that CBP could add acetylation to histones I wondered if it was important in cancer, as we knew that it was often found stuck to a protein called E1A, which was involved in driving cancer.”

To find out if there was a link with disease, Tony teamed up with Carlos Caldas, now at the Cancer Research UK Cambridge Institute. Together they looked at tumour samples and found faults in a CBP -related protein, p300, in many types of cancer.

To Tony the implication was clear – understanding these modifying proteins and the molecules that ‘read’ the histone code could lead to vital new insights into the underlying biology of cancer cells. And, he thought, perhaps interfering with them could be an entirely new way to treat the disease.

From blunderbuss to sniper rifle

Right from the start, Tony has hoped that his work would lead towards the development of more effective treatments for patients. But, as is so often the case with such fundamental biological research, it’s taken a while to get there.

One problem with drugs that target histone modifications is that they are relatively un-specific, although there are several in clinical trials, with two approved for wider use. Histone marks are used throughout our entire genome to control gene activity, even though there may only be relatively few genes that are actually driving the cancer. Attacking them all is like using a pellet-scattering blunderbuss rather than a precision sniper rifle to hit a target – sure, you’ll hit it, but you’ll cause a lot of collateral damage too.

Another important discovery came when Tony and his team revealed that a rogue protein found in a certain type of leukaemia called MLL specifically recognises the histone marks on just a handful of genes, some of which are responsible for driving the cancer. Importantly, the pharmaceutical company GSK had just developed a drug that could specifically target this rogue protein.

Results from tests on cells growing in the lab were impressive – the drug, called I-BET151, brought MLL cancer cells to a standstill, but left healthy cells unharmed. It also turns out that the faulty protein targeted by I-BET151 is also found in a rare tumour called NUT midline carcinoma as well as other cancers, and it’s even turned out to be implicated in heart disease too.  So there could be a much larger group of patients that might benefit from the drug, or others like it.

You can find out more about this exciting story in our short video from 2011:

[youtube=http://www.youtube.com/watch?v=Bh06gKLHFFc]

The drug is now being tested in clinical trials, so we’re keeping our fingers crossed that the promising results from the lab bear out in cancer patients. And Tony and his team are now testing a whole range of drugs that target the proteins that ‘read’ epigenetic modifications, to find more promising treatments for the future.

He says, “There’s a lot of hope, and I think that the epigenetics field is going to generate a lot of good potential drugs to take forward to the clinic. Pharmaceutical companies are making a whole bunch of small molecules, but they need help to validate whether they work in the lab, and which patients they work for – so we are helping them do that.

“And we’re making progress in one important area- cancers’ ability to evolve resistance to these new targeted drugs – and are finding the right combinations of drugs to get round it.”

The future’s bright, the future’s RNA

While some members of his lab continue to focus on histone modifications and the proteins that recognise them, Tony’s quest for discovery has started to lead him in a new direction, towards RNA. This molecule is a ‘cousin’ of DNA, created when DNA is read through a process called transcription.

Conventional biology dogma tells us that RNA is merely an intermediate between the instructions – DNA – and the end products – proteins – as if it were a scrap of paper bearing a recipe that a baker has scribbled down from a library cookbook. But this view is changing fast.

Tony says, “We now know that RNA is so much more than just a ‘messenger’. I believe that it may have much more functionality than protein – it can do all the things protein does, and then some. I think the RNA world is almost completely undiscovered and it’s very exciting.”

Shifting focus to pursue big questions that intrigue him, where there are potentially game-changing discoveries to be made, is a recurring theme in Tony’s lab. And it’s thanks to long-term funding from Cancer Research UK that he’s been able to follow his curiosity and make important findings that could change the way that patients are treated in the future.

“When I took that risk to pursue the cancer gene FOS in the early days, it was my own career I was putting on the line. Now I have people working for me in my lab, and I’m asking them to take that kind of risk too. But I think that to succeed in the current climate you have to take risks, and ask big questions.

“Generally it works out, as I have a good gut feeling about what makes a good risky project. The question I always ask is ‘If I discover something, will lots of people think it’s interesting and important?’ I’m not interested in just adding small details to an existing picture – I want to find out new things.”

Keep on digging

This quest to unearth things nobody knows has driven Tony since he was a child, and it’s fitting that his many years of cutting-edge research should be recognised.

Our Gibb Fellowship is awarded to a handful of the very best researchers who we’ve funded over the long term, and Tony is in enviable company. The other holders are Professor Sir Bruce Ponder, former director of our Cambridge Institute, our chief scientist Professor Nic Jones (previously director of our Manchester Institute), and Professor Chris Marshall, head of the division of cancer biology at The ICR.

The Heinrich Wieland prize is endowed by the Boehringer Ingelheim charitable foundation. Now in its 49^th year, it recognises the contributions of scientists whose careers have helped to shape our understanding of fundamental cell biology. Last year’s recipient, James E. Rothman has just been awarded a share of the 2013 Nobel Prize in physiology or medicine, highlighting the calibre of the winners.

We raise our glasses to Tony in celebration of his achievements, and look forward to seeing what else he will uncover in the coming years.

Kat