Mark Caulfield - Genomics England

Kat - As the cost of DNA reading technology has come down, it's now possible to think about whole genome sequencing on a grand scale, in order to help us understand more about how our genes affect our health. With this in mind, the UK government, in partnership with the NHS, has set up Genomics England - a company aiming to read the genomes of 100,000 people affected by cancer or rare genetic diseases.

I went along to a recent event about this 100,000 Genomes Project, run by the Progress Educational Trust, which aims to promote discussion around research into and use of genetic technologies. One of the panellists was Mark Caulfield, chief scientist for Genomics England. I asked him to explain what the project is all about.

Mark - The 100,000 Genomes Project is sequencing the entire genetic code of people with rare inherited disease, cancer and infections. The goal is to use the entirety of the genetic code to understand the causes of those disorders, and possibly create the opportunities to develop new medicines and new diagnostics in the NHS. And that means that we can combine talents of the whole National Health Service to deliver this programme, working with key partners in the NHS but also, some of the charities like Cancer Research UK who face the diseases we're working on.

Kat - Can you explain to me a bit about the scale of the project? How many people with each type of disease are you recruiting and how is it going to work?

Mark - So, we have split the genome sequencing into two segments - half for rare disease and half towards cancer. In the rare disease, we're including people with severe response to infection because it could be a form of rare disease. What we're actually doing is receiving nominations from the NHS, particularly in the area of rare disease, for specific diseases with diagnostic unmet need. In cancer, to make a difference to the knowledge base, sometimes we will need to sequence quite a large number of people with a cancer to take account to the fact that in the cancer world some tumours don't just have one group of drivers to cause the tumour. They may have multiple different drivers and that means that there is heterogeneity or differences within the cancer population. And so, we need to study a lot of people with cancer to unravel that. And so, we're working with Cancer Research UK and other experts in cancer worldwide such the International Cancer Genomes Consortium so that we will combine our data with international efforts to build a global picture of the architecture of cancer.

Kat - Tell me a bit about the kind of analysis that people will be doing. Is this the entire genome, the whole thing?

Mark - Yes. It is as much as we can read of the 3.3 billion letters that make you who you are, that are blueprint for the colour of your eyes, whether your hair is curly or whether how tall you are. But also, this may contain variations and these variations may create susceptibility to disease. The variation we're focused on will allow us hopefully to develop new insights that will help people with treatment with cancer and to get new diagnoses and, possibly, treatments for rare disease.

Kat - Some of the things that people are concerned about with doing this kind of analysis is that not only might you find some of the key genetic drivers of these diseases but you might find other things as well. How are you coping with that?

Mark - What we've done is developed, with the advice of clinicians and with the full involvement of patients, a limited list of items that will feedback that are in essence findings that we're going to look for. So, these are things with severe consequences that we'll actually go and look for in the genome. So, to give you an example of some of those, if we discover a mutation that you've inherited in your DNA or developed yourself, we will feed back if it could cause a severe cancer or if it could cause familial hypercholesterolemia or high cholesterol. The reason for that is because some of those mutations may cause cancer in very early life and if we knew about them, we wouldn't hesitate to continue to screen the person for that emergence of the cancer and then try and do something about it.

Kat - But if it's a mutation that you can't do anything about, it's probably better than not to know.

Mark - That's not necessarily true, because if you know about these things it may alter the way you live and how you interact with other people and it may alter your health behaviours. So, there are some examples where people have been given findings back about Alzheimer's and even though that can't be changed, they welcome the opportunity to know that information and to be able to make lifestyle modifications, some of which may or may not impact the disease. But actually, by and large, people are very receptive to this information. But in the 100,000 Genomes Project, nobody has to receive anything other than the diagnosis of their disease for which they enrolled. So, they don't have to have any of these other findings given back to them.

Kat - One of the things that you're doing with the rare diseases is looking at parents and their children. There is an issue sometimes that fathers are not necessarily the father of their child. Is there a risk that this kind of information could be uncovered and what would you do about that?

Mark - Yes. It's in your genome and we will know that, but it's not a medical condition. That's not something that we'll be feeding back. The reason is because if the family unit believe they're a family unit, who are we to disturb them? It's not going to affect them medically. And so, it's a possibility which we most likely will discover for some people, but it's not a medical condition.

Kat - Some of the other things people have raised are about, "Whose data is this? Whose genome is this? And who could have access to this kind of very personal data?"

Mark - When people make informed consent to participate in the programme, they donate their DNA. In essence, your genome remains your genome. If you want it back, we will give it back to you either as individual genetic variations on a USB stick or you can pay us some money and we'll give you the whole genome back. But that has to come on a hard drive and we don't have the money for that. So, it's like having your computer given to you because it's 220 gigabytes for genome roughly. In cancer, it's actually bigger because we have to sequence cancer more times to understand it.

Who owns the data from the programme? To make this an open collaborative environment and have open innovation, we've said that Genomics England will own the results of the sequencing and the combination with the clinical data. This is so the researchers, the NHS and indeed, people from industry could work together in open innovation space and then come to us and say, "We think we've got a really good idea to develop a new medicine. We'd like to license it from you." What that does is it changes the atmosphere inside the research collaborative environment to encourage people to actually work together much more closely. And that, we hope will also draw in opportunities for patients because access to that data by industry will encourage them to bring their medicines to the United Kingdom because we'll be able to do stratified healthcare on them.

Kat - One of the things that's increasingly happening is that people are having to grapple with their genomes, with understanding risk, with the understanding that finding a particular genetic variation doesn't automatically mean you'll get a disease. It's about risk and what that means. How are you trying to educate the public about what some of the findings in their genomes actually do mean?

Mark - Well, this is a really important point because we need to grow public understanding of what this means and also, in some measure, demystify the genome. So, we mustn't make it a black box. Patients are fed up with black boxes in medicine and what they really want is for us to open up their genetic code and healthcare. And so, that's what we're going to do. So, working with patients who enrolled in our groups and also, through CRUK, we're working with a number of patient groups to inform the programme, develop the programme. And through our public engagement team, we'll have a number of public engagement events. We are doing similar events around the country, already interacting with the public and patients. Public trust and patient engagement and trust is paramount to the success of the programme and we prize it very highly.

Kat - Looking say, maybe some 5 years into the future, what would you like to see and mark as success for this project?

Mark - A really clear marker of success would be at least new diagnoses given to people with rare disease, affected by rare disease. The possibility of having new stratified medicine - that may take longer than 5 years to develop for cancer. But understanding the architecture of cancer would be hugely useful to trying to prime innovation in that area. And may also allow us to use existing medicines better or get some medicines that are stuck on shelves because we don't know what to do with them and they didn't work in their original diagnostic area off the shelf and given to patients.

Kat - That was Mark Caulfield, chief scientist for
Genomics England.