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How pioneering research will help young patients at Cambridge Children’s hospital

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The head of paediatrics at the University of Cambridge has said he is astounded by research findings that show the high proportion of children in intensive care units and specialist clinics with genetic diseases.

Prof David Rowitch told the Cambridge Independent that the findings – which are being prepared for publication – can help inform how NHS care is delivered in the region and aid the drive towards early detection and diagnosis.

How Cambridge Children's hospital will look. Picture: Hawkins Brown and White Arkitekter
How Cambridge Children's hospital will look. Picture: Hawkins Brown and White Arkitekter

Speaking ahead of an online talk he will give on December 7 about the new children’s hospital due to be created on Cambridge Biomedical Campus, Prof Rowitch said: “We’ve asked the question to what extent is a child going to a neonatal ICU, or a paediatric ICU driven by a genetic disease?

“We found that in the neonatal ICU, it’s one in four babies that have a genetic condition. In paediatric ICU, it’s one in three. And if we go to the neurology clinic – where there may be children with seizures or who may be floppy or who may have some abnormality in the way they walk – about one in two have a genetic condition.

“Now, these are astounding results. We’re seeing these results from our children in the East of England. They’re very similar to what reports in the United States are saying – there’s an unsuspected high burden of genetic conditions in paediatrics.

“I’ve been a paediatrician for 35 years. I’m blown away by this finding. We really didn’t suspect how much of the time genetic conditions are the cause for children who have serious conditions that require them to come to hospital or be seen in specialty clinics.”

Cambridge Children’s, which it is hoped could be in place as early as 2025-26, will pioneer a new approach by integrating physical and mental healthcare alongside world-leading research at the co-located Cambridge Children’s Research Institute.

“In Cambridge, we’ve got a particular story to tell when it comes to how research can help in care because, in our region, there have been fundamental discoveries about the structure and biology of DNA,” said Prof Rowitch, explaining that advanced genomic medicine will be key to aiding diagnoses.

“The research question is: if we’ve made these diagnoses, how can that help children? How does that improve their care? Can it help us understand drugs that might work better for them? But if I had to put in one phrase, our research is overall going to try to focus on this idea of early detection. We think that many diseases start very early – a genetic disease might be something that a baby is born with. So we want to make those tools available straight away.

“Our approach in paediatrics is going to be how we can define the origin of even adult-onset diseases.”

Could identifying the earliest signs of a disease like diabetes, for example, lead to interventions that delay it developing, helping shift the focus to prevention?

“Early detection is a mantra for our research,” noted Prof Rowitch.

Prof David Rowitch, head of the Department of Paediatrics at the University of Cambridge
Prof David Rowitch, head of the Department of Paediatrics at the University of Cambridge

Aiding this process is whole genome sequencing – a technique that examines an individual’s complete DNA data, rather than targeted areas.

With adult cancers, the potential for genetic testing to help identify treatment has now been established for decades. But, typically, the approach is to test for changes on a select group, or panel, of genes.

“If you went to any of the top cancer institutes around the world, you’ll have 500 genes tested in a focused panel approach. And the reason you do this is there are drugs for those 500. And that 500 is the distillation of years of research,” explained Prof Rowitch.

“With children, it’s way more complicated. Children with a serious disease could have any of 8,000 different conditions, so we need to look really comprehensively. We use a gene-agnostic approach. And we essentially look at the entire genome – not only at the genes.

“The genome is made up of both exons – the things that make up the genes – and lots of DNA in between those exons. We look at everything. And the reason is that we find that the kinds of genetic issues affecting children are so heterogeneous.

“Where I think the UK will rapidly outpace approaches being taken in other countries is the fact that the government has invested in whole genome sequencing. It’s a very high-risk and high-cost strategy that UK government has taken.

“By contrast, many of the US top children’s hospitals will use whole exome sequencing. So they’re looking at just the genes.

“We’re finding for certain kinds of conditions, we get about a 10 to 20 per cent better diagnostic rate with the genome than the exome.

“But we still haven’t even begun to look at all the DNA between the genes. We have that information, because we’re collecting it, but we haven’t really started to analyse it yet. There are a lot of clues there that will increase our diagnostic rate as we start to shift our focus to the DNA between the genes.”

But the data that will be available doesn’t stop there.

Another emerging field is the study of epigenetics, which explores how cells control gene activity without changing the DNA sequence. These changes are heritable.

“It’s beginning to be used in certain kinds of cancer – such as paediatric cancers,” said Prof Rowitch.

How Cambridge Children's hospital will look. Picture: Hawkins Brown and White Arkitekter
How Cambridge Children's hospital will look. Picture: Hawkins Brown and White Arkitekter

“In Cambridge, our genetics laboratory for the Eastern region, the Genomic Laboratory Hub, is leading nationally on the uptake of whole genome sequencing for diagnosis of paediatric cancers. And where we would like to go is to add that epigenomic testing on top of that. We would like to bring in even more. The NHS is now also starting to pay for transcriptomic profiling and we think that could also be useful.”

This is the study of the RNA transcripts that are produced by the genome – in other words it explores the messages that control how genes are activated.

“It would be great if Cambridge is the place where these sort of multi-omic approaches can be developed,” suggestsed Prof Rowitch. “We have whole genome. We have epigenome. We have transcriptome. And I think these are realistic if you have a team that is motivated and skilled in these big data approaches. Fortunately, our paediatric cancer team is brilliant.”

Proof of the value of all these techniques will only come with time.

Prof Rowitch noted that our thinking around how stem cells could be used, for example, has matured.

“In the initial days of stem cell hype, there was quite a lot of excitement – without a lot of evidence – that stem cells could be helpful in treating human diseases,” he acknowledged. “If you look honestly at the track record over the past 15 years, where has stem cell therapy really progressed? There are very few examples. I think there was too much enthusiasm, but what has come out of it is that we understand that stem cells can also benefit from gene therapy treatments.”

Patients with the so-called ‘bubble boy’ disease – an immunodeficiency that means exposure to the environment would be fatal – can now be treated with gene therapy directed at stem cells to promote a stronger immune response.

Similar work is being done in the field of sickle cell disease.

“I think that’s where we’re seeing real advances and that approach could also be applied to new treatments for a variety of other disorders,” said Prof Rowitch.

“In my lab now, thinking about Pelizaeus-Merzbacher disease (PMD), we’re working on ways that we could take the same cells that we were working with before – neural stem cells – but using gene therapy approaches to be able to fix the mutation that causes PMD, and then give those cells back to the patient.

“It’s not a replacement approach, we’re trying to rehabilitate and improve the function of the endogenous stem cells that the patient may already have.”

Armed with this array of emerging technologies, Cambridge Children’s promises to be a beacon of hope as researchers and clinicians aim to understand the early origins of disease, improve life trajectories and shift from reactive care to prevention.

Prof David Rowitch will speak online at 11.30am on Tuesday December 7 as part of the CBC on Virtual Tour. Visit the talk’s Eventbrite page to sign up for free.

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