Image credit: Onur Pinar /Wellcome Sanger Institute
In this fourth part of our innovator blog series, we spoke to Dr Iñigo Martincorena, group leader in the Cancer, Ageing and Somatic Mutation programme at the Wellcome Sanger Institute and academic co-founder of Quotient Therapeutics along with Dr Peter Campbell and Professor Sir Mike Stratton. Quotient is a new company built by Flagship Pioneering in partnership with the Sanger Institute that is leveraging Sanger research to innovate the way drugs are discovered.
Innovation takes many forms – from a tweak that improves technology, all the way to the development of new medicines. Translating science is about adapting research, moving our science beyond the lab, or closing gaps in technologies so that it can be used to improve our lives.
Iñigo, it’s not every day that we announce the creation of a new company. It certainly is exciting, but I understand the key to this all is part of your research at Sanger. Can you tell us how it all started?
It certainly is exciting. Our work focuses on understanding somatic mutations - mutations that happen in our tissues as we age. The fact that somatic mutations cause cancer has been known for decades, particularly with the discovery of the first cancer genes in the 1980s.
However, systematically discovering the mutations that are responsible for cancer was not possible until new technologies like next generation sequencing (NGS) enabled studies of full cancer genomes. This didn’t happen until the late 2000s, when some of the first cancer genomes were sequenced here at the Sanger Institute.
This led to an explosion in the field of cancer genomics, becoming accessible to many. Once sequencing cancer genomes started to become more commonplace and less of a basic research question, Sanger started looking for new unexplored areas of work, and that’s when we focused on understanding how somatic mutations occur in normal tissues as we age, and their role in early cancer development and other diseases.
“Once sequencing cancer genomes started to become more commonplace... we focused on understanding how mutations occur in normal tissues as we age, and their role in early cancer development and other diseases... The challenge then was that we didn't have the technologies to be able to see these mutations.”
Dr Iñigo Martincorena,
Group Leader in the Cancer, Ageing and Somatic Mutation programme, Wellcome Sanger Institute
Now, the challenge lies in being able to distinguish real mutations from experimental noise in healthy tissue. While detecting mutations in tumours had become straightforward with next generation sequencing, detecting mutations in healthy cells was not possible with the standard sequencing methods we had at the time. Why? Because the vast majority of somatic mutations in normal tissues are present in single cells or very small, microscopic, groups of cells. The challenge then was that we didn't have the technologies to be able to see these mutations.
You had to develop them
Yes. We started by deep sequencing of very small pieces of tissue first. This led to the discovery that normal tissues such as skin or oesophagus of healthy individuals have a high frequency of somatic mutations in them, including an unexpectedly high number of cancer-causing mutations. We found that, as we age, our tissues become progressively colonised by clones (copies) of cells carrying mutations that enable them to outgrow their neighbours. It was clear to us that understanding this phenomenon better, across tissues and diseases, would likely shed light on the development of cancer, ageing and other diseases.
However, to be able to study this in other tissues, we had to develop more sensitive methods. Working closely with the Research and Development (R&D) team at Sanger, we first developed a laser microdissection method that allowed us to detect mutations present in tiny clones of cells under the microscope. This new technology has allowed us to first study somatic mutations in many different tissues in the last few years. We then developed an even more sensitive method, called Nanoseq, which allowed us for the first time to detect somatic mutations in highly diverse, or heterogeneous groups of cells, by detecting mutations down to single molecules of DNA. This technology is now enabling us to do faster and more sensitive studies of somatic mutations in many tissues and diseases.
“Nanoseq [allows] us to detect somatic mutations in highly diverse groups of cells, by detecting mutations down to single molecules of DNA. This is enabling us to do faster and more sensitive studies in many tissues and diseases.”
Dr Iñigo Martincorena,
Group Leader in the Cancer, Ageing and Somatic Mutation programme, Wellcome Sanger Institute
And it was a team effort?
Both technologies were the result of the collective effort of multiple people - a collaboration between the groups of Peter Campbell, Mike Stratton, my team, and the Sanger R&D team. The development of Nanoseq was led by Rob Osborne, Federico Abascal and Stef Lensing, and we decided to patent it following the advice of our Technology Translation office.
“We are now able to perform somatic mutation studies [to] look at how different exposures, lifestyles, and variables such as smoking, drinking or diet impact the mutation landscapes of our tissues and how this shapes cancer risk.”
Dr Iñigo Martincorena,
Group Leader in the Cancer, Ageing and Somatic Mutation programme, Wellcome Sanger Institute
Since then, we have continued to develop improved versions of the method with full genome coverage, which are allowing us to comprehensively study the landscape of somatic mutations in any tissue sample. For example, we are now able to perform somatic mutation studies on large cohorts of individuals using non-invasive samples and look at how different exposures, lifestyles, and variables such as smoking, drinking or diet impact the mutation landscapes of our tissues and how this shapes cancer risk. We are also able to start investigating whether somatic mutations contribute to a range of other diseases.
So how did Quotient come to be?
I must say we were very lucky. Flagship Pioneering had read several of our papers on different tissues and approached us to work together at a company they were building focused on using somatic mutations for drug development. So the process was very different to most spin-outs, which are initiated by a research lab. I would certainly not refer to myself as an entrepreneur, but we liked Flagship’s ideas and we thought that this could be an exciting way to translate our science into potential new drugs, as well as help push the science of somatic genetics further.
What can Quotient achieve that you could have not achieved in your lab?
There are several differences between academic and industry research. A big one is the end product. Whilst in my research lab our goal is to make fundamental discoveries and advance knowledge, often in the form of scientific papers, for Quotient the goal is to develop new treatments.
Another considerable difference is scale. In academia, funding can be more limited - in my group, we try to make proof-of-principle discoveries, but our resources and expertise are limited to scale them up compared to industry. Quotient has the funding and the breadth of multidisciplinary expertise required to rapidly scale up and translate a discovery. So, I’d say the goals are different but complementary.
What would you say you’ve learned? Has it been a steep learning curve?
At a personal level, I'm enjoying the ride. I’ve been learning how this other side of the world works. Again, I’d reiterate that we’ve been very lucky. If we’d had to build the company from scratch that would’ve been a whole different experience. Flagship is a company builder, they had a vision and they needed our expertise to enable it, which has led to an exciting partnership.
They came with the experience of having built successful companies before. I’ve tried to learn from their experience and they have been learning from ours too. So in that sense, it's been exciting and very formative to learn about how you build a company, and what things to consider. The speed, for example, and the tight timelines in which they operate are wholly different. I'm not necessarily adopting these because they do not apply to our work, but it’s still a very different approach to science and research.
“It's been exciting and very formative to learn about how you build a company, and what things to consider. The speed and the tight timelines in which they operate are wholly different... it’s still a very different approach to science and research.”
Dr Iñigo Martincorena,
Group Leader in the Cancer, Ageing and Somatic Mutation programme, Wellcome Sanger Institute
At a practical level, I don’t have management responsibilities within the company, I’m a scientific advisor. My interactions are not dissimilar to the types of interactions that I would often have within my academic group where I advise in the design of an experiment, interpreting data, refining a method, etc.
We’ve talked about the goal for the company, but what do you want to see Quotient achieve?
The beauty of Quotient is that it is very ambitious, especially in the diversity of diseases they are interested in. It is a broad portfolio, all based on the concept of somatic evolution and normal tissue sequencing.
I would love to see our work being translated into benefit for patients. It’s something I’d never envisioned before, mainly because I work on quite fundamental questions and it was out of my reach. However, now that I see the possibilities, to think that the concepts and the technologies that we have developed could translate into patient benefit has been a source of great excitement for me.
“To think that the concepts and the technologies that we have developed could translate into patient benefit has been a source of great excitement for me.”
Dr Iñigo Martincorena,
Group Leader in the Cancer, Ageing and Somatic Mutation programme, Wellcome Sanger Institute
