Prof Greg Hannon on taking over at the Cancer Research UK Cambridge Institute and creating the world’s first virtual reality tumour
The new director is assembling a team of chemists, biologists, mathematicians, astronomers and VR experts
Greg Hannon conceived of his boldest idea to date while riding his bike.
“A number of years ago back in New York, I had a house upstate in the Catskills,” he recalls. “In a peculiarly anoxic moment of a bike ride at the top of a very large climb, I was thinking about some seminars I had seen by my neuroscience colleagues at Cold Spring Harbor, who were showing these amazing 3D models. I started to think that we really didn’t know the 3D structure of tumours.”
Initially an imaging project, Prof Hannon catapulted his idea somewhat into the realms of science fiction after bringing his lab to the Cancer Research UK Cambridge Institute.
The catalyst was the charity’s announcement that one of the themes of its Grand Challenge fund was challenging researchers to develop a ‘Google Street View’ of tumours.
Prof Hannon’s team won the £20million prize to develop his idea of creating an interactive 3D atlas of a tumour that researchers will be able to ‘fly through’ using virtual reality.
“I thought this is a chance to conceive of a structural investigation of tumours at a whole different level, where we are not just looking at one small type of expression of one gene but where we try to do deep molecular annotation of every cell in the tumour in models that we can manipulate but also in human samples,” says Prof Hannon.
“That kind of concept needed to be a big, highly collaborative project bringing together lots of different skill-sets to do something no-one has ever done before,” he says.
“Even though the project is highly focused on breast cancer, the sort of approaches and techniques we develop will be applicable to other tumour types and will also very likely be applicable to many other biological processes.”
He has likened the feat to putting a man on Mars.
“It’s a technical challenge but doesn’t violate any of the laws of physics,” he says. “It’s possible, we believe, and progress over the last eight months is confirming that conviction.”
Prof Hannon, who joined the Cambridge Institute as senior group leader, took over on February 1 as director from Prof Simon Tavaré, who has led it since 2013.
“I’m tremendously excited,” he says. “It’s a huge opportunity. The institute is a tremendous place to do science. First Bruce Ponder and then Simon Tavaré have really built a world-class cancer research institute. They have left an incredible legacy and my job is to take the institute to even greater heights.”
Creating the world’s first VR tumour will certainly do that. But it is a project of bewildering complexity – and Prof Hannon has seven years to do it.
“Many of the longer funding vehicles operate on a five-year timeline, which I’ve never really understood as it’s seemingly artificial. I made the argument that we really want to do something transformational and new you need a longer time horizon. We settled on seven years. You need a year to get started – you’ve got to hire the right people,” he says.
Prof Hannon is assembling a multi-disciplinary team – adding astronomers and VR experts to the scientists – to combine technologies that can track the movement and fate of cells in living tissue with molecular and genetic information.
“We’ve made a lot of progress getting the Grand Challenge lab up and running,” he says.
“We are constituting a new research group which is physically distinct from any of our individual labs, where the chemists, the astronomers, the mathematicians, the biologists all effectively sit together as a single integrated group and it’s my belief that this is the only possible way to address a problem of this complexity and scale.
“We’ve started to import many of the foundational technologies into Cambridge. Imaging mass cytometry is going quite well in the 2D samples. We’ve made a lot of progress on spatial transcriptomics. We’ve started to make quite a bit of progress with some of the image analysis with some of our astronomy colleagues.”
These methods for analysing cells and cellular components will be brought together to create the virtual tumour - complete with ‘Superman mode’ to enable a fly through. They will help researchers examine what cells are next to each other, how they interact and how they work together to enable tumours to survive and grow.
“It’s enough of a challenge to operate these bleeding edge technologies on their own but we want to go further and combine the information that you can gain from each approach and that ratchets it to a whole new level,” says Prof Hannon. “We have recruited pioneers in many of these measurement methods but also very smart chemists, mathematicians and others.”
Helping with the task of combining data sources are those more used to looking beyond this world.
“Astronomers are often integrating imaging data gathered from different instruments and each of them has errors that distort the images in different ways, so they have to do a lot of realignment, in a similar way to what we are looking at,” says Prof Hannon.
“As it turned out, they are also very experienced at moving, storing and manipulating very large amounts of imaging data.”
Doctors with different expertise in different parts of the country will be able to immerse themselves simultaneously in the 3D tumour world created.
“It’s not just the 3D component of it – it’s also about looking at many different cell types. People tend to study the tumour micro-environment and will often look at cell types but we’re trying to look at them all at once,” says Prof Hannon.
From exploring the distribution of mutations to imaging the antibody signals, this phenomenally detailed creation could unlock critical new insights in tumour biology.
“We are looking for patterns – the spatial relationships between cells providing, for example, gene expression or protein activity signatures that tell you these cells are interacting in a particular way and, for example, creating an immunosuppressive environment,” says Prof Hannon.
“The hope is that will give us some predictive power but also some opportunities for intervening in how those cells interact or the outcome of that interaction. We hope some version of this will become a new pathological tool in the clinic.”
It’s a vision of the biopsy of the future.
“In those cases you would have a high throughput method gathering information on critical biomarkers,” he suggests.
“I think what we’re doing with the Grand Challenge is trying to answer some very specific questions about breast tumour biology but also building a platform that I think will serve the Cambridge community much more broadly.”
And the project fits in with how Prof Hannon sees the CRUK Cancer Institute furthering our understanding of cancer biology under his leadership.
“We’re thinking about tumours not as monolithic entities but as heterogeneous collections of cells. I think about this in terms of tumour ecology and evolution – understanding communities of tumour cells that exist within an individual cancer and how those interact with the normal cells of patients.
“That’s certainly something the Grand Challenge is focused on. We are well-positioned to embrace the complexity of tumours.”
A history of innovation
The Hannon lab is renowned for its innovation and has created technologies now in use around the world by researchers.
“In my opinion, biology is almost always technology limited,” observes Prof Hannon. “You see new technology emerge and fields explode. Some of the things we’ve done in the past have had that impact,” says Prof Hannon.
Among the technologies developed by the lab is exome capture – a method used to extract and sequence the exome, which forms about one per cent of the total genome but contains all the protein-coding genes and about 85 per cent of mutations.
“That’s now used quite heavily for sequencing patient samples in the clinic,” says Prof Hannon. “Not long after we developed that approach it became important for mapping disease genes. Whole genome sequencing at that time was too expensive.”
The Hannon lab has a long interest in research non-coding RNAs – ribonucleic acids that are not translated into proteins. It is thought there are thousands of types of them and some play important roles in disease, including cancer and Alzheimer’s.
“I trained as an RNA biologist as a PhD student then went to Cold Spring Harbour to work on cell cycles and cancer,” says Prof Hannon, adding that he came into the field of non-coding RNA “somewhat accidentally” after witnessing the emergence of RNA interference – the process by which these molecules inhibit gene expression.
“Initially we tried to use it as a tool to probe the cancer problem but it became very clear that in order to make that a powerful tool we had to understand the underlying mechanisms,” says Prof Hannon.
In recent years, the lab has explored the role of small RNAs in protecting the genetic information in germ cells – those that turn into sperm or eggs - from molecular parasites.
“It’s a fascinating problem - how do animals discriminate their own genes from genetic material contributed by genetic parasites?” says Prof Hannon.
The lab has shown that small RNAs transmit information from one generation to the next. Could they have unlocked one of the secrets of evolution then?
Prof Hannon won’t go that far.
But he says: “They can be a mechanism of epigenetic inheritance, where the genomic experiences of their parents are passed by RNAs as information to offspring to enable them to combat the same elements.”
Videos by Suil interactive Ltd and IMAXT Grand Challenge Group