We met with Chris Wigley, CEO and Sir Mark Caulfield, Chief Scientist at Genomics England, at the first Genomics England Research conference taking place in November 2019 in London. We started by asking them how Genomics England is getting on with their objectives.

Chris Wigley will also be speaking at the Festival of Genomics this January. You can register HERE before tickets run out!

Where is the Genomics England project at and what has it found out so far?

Sir Mark: In 2013, Genomics England was founded and asked to sequence 100,000 genomes, and we completed that milestone on the 5th December 2018. We’ve now returned 102,000 genomic analyses to the National Health Service (NHS), and they’re working with that data to bring diagnoses to patients.

Today, 1 in 4 or 1 in 5 people with a rare disease are getting a new diagnosis from this, and in the cancer programme it’s potentially the case that up to half could get the opportunity to participate in a trial.

Lately, we’ve begun to analyse patient genetics to detect if a medicine could be potentially harmful for them. This is pharmacogenetics, where a variant in the genome could make someone susceptible to a medicine and cause an adverse reaction. We’ve started feeding the information back since April for some quite severe reactions to cancer therapies. This is a prelude to the NHS having a systematic approach to pharmacogenetics.

Chris: We’re at a point now where the participants are able to engage over time with the diagnostic yield that is generated from that data, so it’s not like this is a one time opportunity.

For instance, all 600 researches who are in the room today continue to generate new insights between what’s going on in your genome and something that’s going on as a human being over time. We’re already learning things today every day that we didn’t know 3 or 4 years ago.

I think that one of the important messages that we’re passing back to participants through our partnership with the NHS, is that if we don’t have a specific result for you today – for example you have X or Y syndrome – that doesn’t mean that in a year or two there still won’t be one. We’re continuing to get new insights that we can feed back into the system over time. We’re effectively giving participants an ongoing subscription into insights as generated by the research community.

In these insights, there was a case where dietary intervention was transformational for a patient. Often, we’re assuming there’s a whole raft of drugs that a patient will take, when simpler methods such as diet can have transformational effects. Can you give us some examples of other simple interventions?

Sir Mark: The Secretary of State, Matt Hancock, spoke about a child who had developed intractable epilepsy. So, by the time you sat in the room this morning, she would have had several seizures and become locked in. She was beginning to build up problems with balance and the ability to support herself, and her mother feared she would be in a wheelchair and might even perish.

She was enrolled in the programme and discovered that she had a deficiency of GAMT, and by supplementing her diet with 3 amino acids, she had a complete reduction in her seizures has begun to communicate and respond facially with smiling, which is a big thing for someone who thought there was no hope for their child.

There is also a child in the programme who was admitted to the intensive care unit with changes in his nervous system and severe infections, which no one could figure out what the cause was. After numerous tests, the cause remained unknown and he sadly passed away at 4 months. The parents wanted to know the cause so they could decide on the risks with having other children, so they enrolled in the programme to provide answers for their reproductive health.

After an unexpected pregnancy, tests showed that there was a change in a B12 transporter intake from the blood stream inside cells. Other children with similar variations receive high doses of B12 injections weekly, which is simple and cheap. Once the second sibling was born, he was tested within one week and was sadly affected. He was treated with high dose vitamin B12, and you’d notice he’s a bit slower than normal but still a happy chappy and has never been to the ITU.

This is not going to be the case for everybody though, I need to emphasise that. As Professor Goldstein (the founding Director of the Institute for Genomic Medicine at the Columbia University Medical Center) said earlier, our jobs as scientists allow us to build a living ecosystem to convert information – not to simply diagnose, but to take that additional step into what we can do to create a treatment. Sometimes it might be simple and dietary, and some other times it might be more complex.

Chris: As we start to move beyond 100,000 genomes and into the next chapter, particularly through work such as the 5 million genomes programme and new-born cohorts, new information gives us the possibility to get ahead. If we’re understand what’s happening within the genome and beyond, before someone presents symptoms we could be giving them B12 or a high fat diet, or implementing an exercise regimen according to their genome. We can support that wider NHS mission around health rather than illness, and how we can promote health rather than cure illness.

Professor Goldstein earlier said that 1 in 20 people in the general population may have a mutation that might be linked to a potentially deadly disease is that correct?

Sir Mark: It’s about right. 1 in 17 is what we would say. That means around 3 million people in the UK potentially have a rare disease. I think what he was alluding to in some case is that we don’t understand why people may possess the changes that suggest they would have a disease, and yet don’t manifest it. That might mean there’s another factor at play in their genome that’s modifying the importance of that, and we would be able to find out that information eventually with whole genomes.

Chrs: Also, there are other factors in play. Genes are not our destiny. If something is happening in one gene, something else may be happening in another gene that counteracts it. These genes are not a direct 100% causal link to disease, other than very rare monogenetic cases like sickle cell anaemia.

There’s that interesting mindset shift that, and as we understand both about the genome and also the relationship between the genome and lifestyle, there’s that thought that says every disease is a rare disease because you have it and therefore it will present differently in you as a human being then in would in someone else. Even things we think of as a disease like breast cancer, we know there are multiple types of breast cancer including those rarer sub-types.

Part of the benefit of these new waves of technology, both on the digital diagnostics in genomics and other omics’ sides, is that we start to de-average disease. A parallel of this can be seen in marketing where TV adverts go out to everyone, but now on the internet you have specialist trade publications and receive targeted advertising to the individual. In healthcare, we have a standard of care for everyone who has disease X. Now we can start to deaverage and disaggregate diseases and get to personalised interventions that are more effective for the individual patient.

Going back to 1 in 17 figure, has that been born out of your research and has any of your research confirmed that?

Sir Mark: That’s pre-existing. You can find that in the UKs rare disease strategy. It’s difficult to answer if the research has confirmed that because we’re collecting families with rare diseases who – by definition – clinicians decided that have a rare disease. They are a slice of the population so I can’t say how reflective we are. But we’ve enrolled against 1200 disorders that were nominated and defined with a diagnostic unmet need by the NHS, researchers or industry partners in medicine because they had a medicine where they wanted to understand more about the biology of the disease to make that medicine better.

Chris: In terms of working towards 5 million in the next chapter of cohorts, with setting up pilots or elite wave programmes or new-born screening, because it’s a larger number they become more representative of the whole population. But on this topic of representative data, there is also a great opportunity to increase the diversity of the genomes in the data set. We can do that partly through a better engagement with other communities in the UK, such as Asian, East Asian, African, or other populations as they may respond very differently to treatments.

It’s important when we think about equity of access to the best healthcare in the UK, and now we have that opportunity to bring in more genetic diversity from the UK population to understand pharmacogenomics better and engage in international partnerships. We’re in conversations with Qatar, India, Singapore and other countries around the world. Once we start to bring these data sets together, we can start to get to those rich insights than we get from just looking at the white British population or Caucasian European genomes.

Does the increasing need to handle vast amounts of data mean that shift in things balance of skills set within Genomics England?

Chris: Yes, that’s true. This entire ecosystem we’ve needed to build has required a sort of upscaling skill evolution, and that goes all the way from the multidisciplinary teams that interact with patients, through to the specialised outfits like Genomics England. We’ve grown up with a very strong emphasis of bioinformatics as the core sophisticated technology element of what we do. We now have a very large team around data architecture, cloud architecture, data storage, protocols.

You previously said something about how you wanted all new-born heel prick tests replaced potentially with genomic testing. Is there a chance that in a few years there is a programme for this?

Sir Mark: What we said when we launched Salisbury centre, and we continue to develop this, is that the moment was right for a societal and ethical debate on whether we could improve on the heel prick test. The heel prick test is done within a few days of birth and tests for 9 different things. At Genomics England, we think we can do better than that, but we need to prove it.

We would carry out a research programme under the auspices of informed consent, so people would make a choice to be involved in the programme. Then we would take the appropriate sample to do a whole genome test. We would probably need to do a pilot test because we need to understand the parents and healthcare professionals’ views.

This has not been done anywhere in the world yet. There are other countries who are thinking about doing it. We have done some work which suggests but there are 700,000 live births in the UK and possibly as many 1 in 260 of those births might have something in their genetic code, whereas through a relative simple intervention (that could be dietary as we discussed earlier) we could make a difference, or at the very least reduce somewhat the disability. Possibly even allow them to live a more normal life and in some avoid harm. We don’t have evidence that will work at all, we need to do a research programme with new-borns prove this and compare with the standard heel-prick test.

Is that a pilot you are planning?

Sir Mark: We are looking at that at the moment, and hope to begin our work on that over the course of the next year. But this is not something that you can start tomorrow. This requires the careful laying of preparatory ground. We have to bring public and patients with us, so there is a big ethical and societal debate about because this has not been done.

Chris: As much as we still need to understand the fundamental science, we also need to understand what we communicate back to patients in what way and it’s important.
Some of the concerns in this area include what if everyone finds out – for example – that they are more likely to develop a particular type of cancer, such as bowel cancer or breast cancer. We know depending which way you look at the stats, they can sound scary if you’re not a statistician or bioinformation or scientist – for instance, If you have the BRCA1 mutation that leads to an increases risk of breast cancer.

However, the overall risk of breast cancer even for people with that mutation remains low, and so there’s a risk of over-diagnoses and over-response to a diagnostic risk or probability or chance. If I think about the typical genome that is passed through the bioinformatics workflow as part of the 100,000 genomes project, we might get up to a million insights about those 6 billion letters coming out of the pipeline. The magic is in how you rank those million insights – those million points of difference versus the “normal genome”. Which ones are actionable, which can we do something about, and which maybe are non-actionable but helpful to explain to someone so that they know which ones are not being communicating about at all? Paternity is a prime example of this. Some of the commercial genomics companies have worked very hard on how they communicate this information back to members of the public who are engaging with it for the first time.

Any idea on the size of the pilot?

Sir Mark: We’ve looked at how we could power this a pilot study and it would need to be more than 10,000. Probably 20,000. We think we could answer this question possible with a cohort around 180-200,000. We’ve done work on this and we’ve got to be able to answer why we’re asking for the money. We are just not settled on a precise number for the pilot, but 10-20,000 would be needed to get enough cases to show that you can detect things. The pilot cohort will be a small sub-set of what will eventually be 200,000 people.

Chris: Ultimately, do the mental arithmetic scaling up to the whole population. Mark mentioned earlier about 700,000 births a year. We need to ask ourselves two questions. 1) The penetrance question i.e. if we can see a change in the genome is that definitely going to result in a change in the person’s experience? And 2) Can we do anything about it?
When both of those questions are a clear yes, that’s where we get to the 1 in 250, 1 in 260, which is about 4 in 1000. If we take 700,000 births, and allow for some opt outs, you could say there’s actually 3,000 people a year whose lives we could transform for the better by doing this, and that’s just in these early onset high penetrance cases.

Sir Mark: There are some conditions where the presentation of the genetic change is not guaranteed. It’s variable. So those are the ones we’re not focussing on because we’re not certain what to do with those. We’re focussing on the ones that are highly likely to cause a problem and a problem early in life. It is our aim at some point early next year to begin to do this.

What would you hope to achieve by running the pilot like this and what is the best thing you could imagine?

Sir Mark: We would like to understand whether a whole genome analysis conducted close to birth could inform how we could avoid harm for a child.

The pilot suggests tackling things that come in before the age of 5. But you’re saying the end game could help things at the other end of the spectrum?

Sir Mark: We’ll have lifelong health benefits, and there will be other things we’ll be able to find out. We want to show that there is a new opportunity for children in our nation to have something that stops some of the worst diseases. 1/3 children with a rare disease will die before their 5th birthday. That’s why we’ve chosen 5 years. We want to change it forever and because of what been done, we have the platform to take that on in a way that other nations may not.

Chris: The great thing about the work that we do with the NHS around the equity of access. This is not just for the rich and not just for the tech savvy. It’s for everyone we thing about. What we’re talking about here is a free lifelong subscription data-enriched relationship with the health service. That starts at birth, but the more data we have about a person and the more we build that relationship data enriched health service, the better insights we can generate and do something profoundly fundamentally to someone. It could recommend a health intervention that might save or improve lives. Having a free subscription for life for the benefits we can get from genomic data is amazing. It’s not a one-shot interpretation. It’s a relationship with your genome and with your data for life.

If you didn’t have your genome sequenced and analysed at birth, could you go see an GP in 2020 and have it done?

Sir Mark: Suitable access to this technology is our absolute core principle here, so we would have to look at how everything comes about. Particularly, if one was to roll this out to a broader section of the new-born population, we obviously have parental choice. You might make choices at age 20 that your parents wouldn’t have felt able to because of the knowledge you have and because of the decision others have made.

Chris: I think it’s important to look at the new-born part of this. It’s an important part of it, but it’s important to look at that lifelong relationship. For example, Mark talked about adverse response to drugs and pharmacogenomics. We can use this information for someone if we’re really casting ourselves into the future. Someone may have had their genome sequenced and 25 years later they develop another health problem. We can use the same genomic data to assess if they are likely to have an adverse reaction to a drug and help them get onto a treatment path or therapeutic to give them the best chances of a good outcome. The benefits of this can play out over the whole of someone’s life.

Even over someone’s later life? In their latest years?

Chris: Yes. For instance, with Alzheimer’s disease, which is very late onset, we can start to generate insights about how someone is likely to respond to different treatments which they may encounter when they are 75 from the moment their born. For me, this is one the most mind-blowing things of these insights we can derive from the genome. I think it’s worth pointing out that with the insights generated through the 100,000 genomes project, the NHS has already launched multiple genomic tests under the genomic medicine service to begin early next year. There is national test directory where doctors can effectively on their screens and get a list of known genetic genomic tests that they can bring.

When will I be able walk into my GP, and they’ll say let’s sequence your whole genome?

Chris: That could be happening from next spring. But it wouldn’t be your GP. You would be referred to a hospital to get the test ordered. However, if you have a condition for which there is a strong relationship with your body as you experience it and with something happening in your genome, that’s already there. One of our goals is to keep expanding that test directory.

Sir Mark: The test directory mostly consists of rare inherited diseases – that’s this 1 in 17 that we talked about earlier, as well as cancer. We created a national test directory, re-profiled 300,000 tests and changed 25% of those tests to newer tests. So, for rare diseases and cancer we have that to offer.

Why is it rare disease and cancer? Because these are tractable to healthcare. Again, if the symptoms match those disorders, it’s appropriate you could be eligible for whole genome sequencing starting next year. But now there’s the availability of a whole repertoire of genomic tests with access across the whole of England for the first time. It’s not whole genome at the moment but it soon will be.

If you go in today to your GP and say I want a particular type of genomic test for a common complex disease, your GP won’t have that on the list of tests they can order. But the NHS is going to start doing some work on Polygenic Risk Scores, using the aggregate variance that contribute to a common disease to try and estimate the risk you might be at. These are still areas of research endeavour and they need further work before they go live in the health system, but the NHS have indicated an interest in working with the accelerating detection disease to look at this.

Chris: If we can see this change in the genome, is that definitely going to result in an outcome as a human being? There are some things which are monogenetic like sickle cell anaemia – one tiny change in your gene and you definitely have sickle cell anaemia. There are other things like eye colour which is oligogenic, where a small number of genes together determine these traits. There are some polygenetic traits like height. We can predict someone’s height as an adult based on the position or status of a broad number of genes, and by combining all of those changes across the whole genome we can get to a prediction of height.

The people who do this work say you can predict plus or minus an inch of someone’s height as an adult with a high level of certainty. With rolling out polygenic risk scoring across a population, we can start to use this technology where there are lots of small changes across the genes of someone, to get to a risk score for things like heart disease or neurodegenerative disease – different types of conditions. That’s much earlier in the research cycle then what we talked about earlier. But it’s an area with lots of investment, interest and programmes like the Accelerating Detection of Disease programme which is launching in the coming months and years in the UK. We’re going to start seeing this more in the mainstream.

Going back for a second to the pilot for new-borns, what sort of timeframe are you looking at? If it went well, when could it be potentially rolled out? 5 years? 3 years?

Sir Mark: Quite difficult to say. We don’t really know how quickly. We’re aiming at 3-5 years assuming everything goes well, as we’re doing something that no one else has done before.

Chris: Born optimist, I would say! Or born impatient.

Sir Mark: If you want health professional and patients to join you, you’ve got to do the groundwork. You can’t suddenly decide to do this and start it tomorrow. You’ve got to get a lot by. If there is anything you know about us after the last 6 years if we’re given a task, we do it.

Chris: Boom.

 

Don’t miss Chris Wigley speaking at the Festival of Genomics this January 30th.

If you haven’t already registered, you can register HERE!