̽��ֱ�� of Cambridge - Rare diseases

Rare disease research at Cambridge receives major boost with launch of two new centres

cjb250 — Mon, 22 Apr 2024 23:34:17 +0000

̽��ֱ��virtual centres, supported by the charity LifeArc, will focus on areas where there are significant unmet needs. They will tackle barriers that ordinarily prevent new tests and treatments reaching patients with rare diseases and speed up the delivery of rare disease treatment trials.

̽��ֱ��centres will bring together leading scientists and rare disease clinical specialists from across the UK for the first time, encouraging new collaborations across different research disciplines and providing improved access to facilities and training.

LifeArc Centre for Rare Mitochondrial Diseases

Professor Patrick Chinnery will lead the LifeArc Centre for Rare Mitochondrial Diseases, a national partnership with the Lily Foundation and Muscular Dystrophy UK, together with key partners at UCL, Newcastle ̽��ֱ�� and three other centres (Oxford, Birmingham and Manchester).

Mitochondrial diseases are genetic disorders affecting 1 in 5,000 people. They often cause progressive damage to the brain, eyes, muscles, heart and liver, leading to severe disability and a shorter life. There is currently have no cure for most conditions, however, new opportunities to treat mitochondrial diseases have been identified in the last five years, meaning that it’s a critical time for research development. ̽��ֱ��£7.5M centre will establish a national platform that will connect patient groups, knowledge and infrastructure in order to accelerate new treatments getting to clinical trial.

Professor Chinnery said: “ ̽��ֱ��new LifeArc centre unites scientific and clinical strengths from across the UK. For the first time we will form a single team, focussed on developing new treatments for mitochondrial diseases which currently have no cure.”

Adam Harraway has Mitochondrial Disease and says he lives in constant fear of what might go wrong next with his condition. “With rare diseases such as these, it can feel like the questions always outweigh the answers. ̽��ֱ��news of this investment from LifeArc fills me with hope for the future. To know that there are so many wonderful people and organisations working towards treatments and cures makes me feel seen and heard. It gives a voice to people who often have to suffer in silence, and I'm excited to see how this project can help Mito patients in the future."

LifeArc Centre for Rare Respiratory Diseases

Professor Stefan Marciniak will co-lead the LifeArc Centre for Rare Respiratory Diseases, a UK wide collaborative centre co-created in partnership with patients and charities. This Centre is a partnership between Universities and NHS Trusts across the UK, co-led by Edinburgh with Nottingham, Dundee, Cambridge, Southampton, ̽��ֱ�� College London and supported by six other centres (Belfast, Cardiff, Leeds, Leicester, Manchester and Royal Brompton).

For the first time ever, it will provide a single ‘go to’ centre that will connect children and adults with rare respiratory disease with clinical experts, researchers, investors and industry leaders across the UK. ̽��ֱ��£9.4M centre will create a UK-wide biobank of patient samples and models of disease that will allow researchers to advance pioneering therapies and engage with industry and regulatory partners to develop innovative human clinical studies.

Professor Marciniak said: “There are many rare lung diseases, and together those affected constitute a larger underserved group of patients. ̽��ֱ��National Translational Centre for Rare Respiratory Diseases brings together expertise from across the UK to find effective treatments and train the next generation of rare disease researchers.”

Former BBC News journalist and presenter, Philippa Thomas, has the rare incurable lung disease, Lymphangioleiomyomatosis (LAM). Her condition has stabilised but for many people, the disease can be severely life-limiting. Philippa said: “There is so little research funding for rare respiratory diseases, that getting treatment - let alone an accurate diagnosis - really does feel like a lottery. It is also terrifying being diagnosed with something your GP will never have heard of.”

Globally, there are more than 300 million people living with rare diseases. However, rare disease research can be fragmented. Researchers can lack access to specialist facilities, as well as advice on regulation, trial designs, preclinical regulatory requirements, and translational project management, which are vital in getting new innovations to patients.

Dr Catriona Crombie, Head of Rare Disease at LifeArc, says: “We’re extremely proud to be launching four new LifeArc Translational Centres for Rare Diseases. Each centre has been awarded funding because it holds real promise for delivering change for people living with rare diseases. These centres also have the potential to create a blueprint for accelerating improvements across other disease areas, including common diseases.”

Adapted from a press release from LifeArc

Cambridge researchers will play key roles in two new centres dedicated to developing improved tests, treatments and potentially cures for thousands of people living with rare medical conditions.

̽��ֱ��new LifeArc centre unites scientific and clinical strengths from across the UK

Patrick Chinnery

Alexander_Safonov (Getty)

Woman inhaling from a mask nebulizer

̽��ֱ��text in this work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

Yes

No deal Brexit could have detrimental impact for four million people in UK living with a rare disease

cjb250 — Fri, 11 Dec 2020 23:30:12 +0000

One in 17 UK citizens lives with a rare disease, which are defined as conditions that affect fewer than one in 2,000 people in the general population. A group of experts has written to ̽��ֱ��Lancet highlighting their concerns about the detrimental impact a no deal Brexit will have on these individuals.

“Rare diseases are rare, and experts are rarer still,” said Dr Marc Tischkowitz from the ̽��ֱ�� of Cambridge, who helped coordinate the letter. “European Reference Networks were set up because no single country has the expertise or resources to cover all of the known rare diseases, which number in the thousands. They’ve played a pivotal role in harnessing the collective knowledge across the continent and in developing sustainable healthcare to treat those affected.”

̽��ֱ��UK has been at the forefront of the creation and development of these virtual networks, which involve healthcare providers across Europe. As a result, write the experts, it has been able “to reap the benefits of closer collaboration with experts and patient advocates throughout Europe”.

̽��ֱ��ERNs have made it much easier to develop guidelines, create disease registries, build research collaborations, and create new education and training programmes. Crucially, they have directly improved patient care by establishing a pan-European platform that brings international experts together to advise on patient-specific complex problem and therapeutic options where insufficient expertise exists in one country alone.

Dr Tischkowitz added: “Leaving the EU without an agreement on UK participation in the Networks means we potentially write off years of progress made by UK clinicians, researchers and patient advocates, while also reducing access to clinical trials and funding. Most importantly, it will diminish our ability to provide the best care for the millions of children and adults with rare diseases and complex conditions in the future.”

̽��ֱ��letter has a total of 73 signatories, including 20 signatories each representing a patient support group and 53 signatories from senior clinicians and researchers who are currently members of a European Reference Network and who will be removed from the networks as of 1 January if no agreement is reached.

Allison Watson co-founded Ring20, a charity that supports people living with ring chromosome 20 Syndrome, an ultra-rare disease that affects her young adult son. She is also a co-lead for the EpiCARE ERN for rare and complex epilepsies.

“I have been hugely encouraged by the change that being part of an ERN can bring, for people like my son and many others living with ultra-rare diseases,” said Watson. “I believe we would not have managed this working with just UK rare disease organisations.”

Initiatives already delivered through the EpiCARE ERN include heightened awareness of rare epilepsies (including ring chromosome 20 Syndrome) across the 28 EpiCARE centres, long overdue Orphanet updates, increased information and education to healthcare practitioners and patient families in the form of leaflets and patient journeys, plus updated Clinical Practice Guidelines which aim to simplify and speed up diagnosis and improve care through understanding the unmet needs.

Watson added: “With thousands of rare diseases, many of them ultra-rare where only a handful of people living in the UK are affected, is it cost-effective or even possible that the UK can deliver effective services and research alone for these people alone? I believe only through collaboration with our European partners and others around the world can we truly meet the needs of the affected and ultimately improve their outcomes and quality of life.”

Beverley Power, chair of CDH UK, the congenital diaphragmatic hernia support charity, says that one of the main barriers to research within the field of rare diseases is access to patients and patient data.

“Since joining the ERNICA European Reference Network, the access to patients and data has become broader for the UK and the rest of Europe,” she explained. “It has enabled charities like CDH UK to better understand other healthcare settings and to be able to signpost newly diagnosed parents and patients with ongoing medical needs in a much better direction. It has also introduced new and innovative ways to collaborate in order to effect better outcomes and quality of life for patients and their families, which ultimately can potentially impact the economic implications of treating rare diseases in the UK and overseas.”

Reference
Tischkowitz, M et al. A no-deal Brexit will be detrimental to people with rare diseases. Lancet; 12 Dec 2020; DOI: 10.1016/S0140-6736(20)32631-3

Correspondence pieces represent the views of the authors and not necessarily the views of ̽��ֱ��Lancet or any Lancet specialty journal. Unlike Articles containing original research, this Correspondence was not externally peer reviewed.

Experts have warned that a ‘no deal’ Brexit will result in the exclusion of the UK from the 24 European Reference Networks (ERNs) that were established to improve the care of patients bearing the lifelong burden of a rare disease, which require highly specialised diagnosis and treatment.

Rare diseases are rare, and experts are rarer still. European Reference Networks were set up because no single country has the expertise or resources to cover all of the known rare diseases, which number in the thousands

Mark Tischkowitz

Tumisu

Brexit

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

Yes

Licence type:

Public Domain

Genomes front and centre of rare disease diagnosis

Anonymous — Wed, 24 Jun 2020 16:15:38 +0000

A research programme pioneering the use of whole genome sequencing in the NHS has diagnosed hundreds of patients and discovered new genetic causes of disease. Whole genome sequencing is the technology used by the 100,000 Genomes Project, a service set up by the government to introduce routine genetic diagnostic testing in the NHS.

̽��ֱ��results of the study, published in the journal Nature, demonstrate that sequencing the whole genomes of large numbers of individuals in a standardised way can improve the diagnosis and treatment of patients with rare diseases. It was led by researchers at the ̽��ֱ�� of Cambridge together with Genomics England.

̽��ֱ��researchers studied the genomes of groups of patients with similar symptoms, affecting different tissues, such as the brain, eyes, blood or the immune system. They identified a genetic diagnosis for 60% of individuals in one group of patients with early loss of vision.

̽��ֱ��programme offered whole-genome sequencing as a diagnostic test to patients with rare diseases across an integrated health system, a world first in clinical genomics. ̽��ֱ��integration of genetic research with NHS diagnostic systems increases the likelihood that a patient will receive a diagnosis and the chance that a diagnosis will be provided within weeks rather than months.

“Around 40,000 children are born each year with a rare inherited disease in the UK alone. Sadly, it takes more than two years, on average, for them to be diagnosed,” said Willem Ouwehand, Professor of Experimental Haematology at Cambridge, the National Institute for Health Research BioResource and NHS Blood and Transplant Principal Investigator. “We felt it was vital to shorten this odyssey for patients and parents.

“This research shows that quicker and better genetic diagnosis will be possible for more NHS patients.”

In the study, funded principally by the National Institute for Health Research, the entire genomes of almost 10,000 NHS patients with rare diseases were sequenced and searched for genetic causes of their conditions. Previously unobserved genetic differences causing known rare diseases were identified, in addition to genetic differences causing completely new genetic diseases.

̽��ֱ��team identified more than 172 million genetic differences in the genomes of the patients, many of which were previously unknown. Most of these genetic differences have no effect on human health, so the researchers used new statistical methods and powerful supercomputers to search for the differences which cause disease – a few hundred ‘needles in the haystack’.

“Our study demonstrates the value of whole-genome sequencing in this context and provides a suite of new diagnostic tools, some of which have already led to improved patient care,” said Professor Adrian Thrasher of the UCL Great Ormond Street Institute of Child Health (ICH) in London.

Using a new analysis method developed specifically for the project, the team identified 95 genes in which rare genetic differences are statistically very likely to be the cause of rare diseases. Genetic differences in at least 79 of these genes have been shown definitively to cause disease.

̽��ֱ��team searched for rare genetic differences in almost all of the 3.2 billion DNA letters that make up the genome of each patient. This contrasts with current clinical genomics tests, which usually examine a small fraction of the letters, where genetic differences are thought most likely to cause disease. By searching the entire genome researchers were able to explore the ‘switches and dimmers’ of the genome – the regulatory elements in DNA that control the activity of the thousands of genes.

̽��ֱ��team showed that rare differences in these switches and dimmers, rather than disrupting the gene itself, affect whether or not the gene can be switched on at the correct intensity. Identifying genetic changes in regulatory elements that cause rare disease is not possible with the clinical genomics tests currently used by health services worldwide. It is only possible if the whole of the genetic code is analysed for each patient.

“We have shown that sequencing the whole genomes of patients with rare diseases routinely within a health system provides a more rapid and sensitive diagnostic service to patients than the previous fragmentary approach, and, simultaneously, it enhances genetics research for the future benefit of patients still waiting for a diagnosis,” said Dr Ernest Turro from the ̽��ֱ�� of Cambridge and the NIHR BioResource.

“Thanks to the contributions of hundreds of physicians and researchers across the UK and abroad, we were able to study patients in sufficient numbers to identify the causes of even very rare diseases.”

Although individual rare diseases affect a very small proportion of the population, there exist thousands of rare diseases and, together, they affect more than three million people in the UK. To tackle this challenge, the NIHR BioResource created a network of 57 NHS hospitals which focus on the care of patients with rare diseases. Nearly 1000 doctors and nurses working at these hospitals made the project possible by asking their patients and, in some cases, the parents of affected children to join the NIHR BioResource.

“In setting up the NIHR BioResource Project, we were taking uncharted steps in a determined effort to improve diagnosis and treatment for patients in the NHS and further afield” said Dr Louise Wood, Director of Science, Research and Evidence at the Department of Health and Social Care.“This research has demonstrated that patients, their families and the health service can all benefit from placing genomic sequencing at the forefront of clinical care in appropriate settings.

Based on the emerging data from the present NIHR BioResource study and other studies by Genomics England, the UK government announced in October 2018 that the NHS will offer whole-genome sequencing analysis for all seriously ill children with a suspected genetic disorder, including those with cancer. ̽��ֱ��sequencing of whole genomes will expand to one million genomes per year by 2024.

Whole-genome sequencing will be phased in nationally for the diagnosis of rare diseases as the ‘standard of care’, ensuring equivalent care across the country.

̽��ֱ��benefits include a faster diagnosis for patients, reduced costs for health services, improved understanding of the reasons they suffer from disease for patients and their carers and improved provision of treatment.

Reference:
Turro E et al. ‘Whole-genome sequencing of patients with rare diseases in a national health system.’ Nature (2020). DOI: 10.1038/s41586-020-2434-2

Adapted from an NIHR press release.

Cambridge-led study discovers new genetic causes of rare diseases, potentially leading to improved diagnosis and better patient care.

This research shows that quicker and better genetic diagnosis will be possible for more NHS patients

Willem Ouwehand

National Human Genome Research Institute, National Institutes of Health

DNA Double Helix

Yes

Licence type:

Public Domain

Snip, snip, cure: correcting defects in the genetic blueprint

lw355 — Fri, 14 Jul 2017 08:01:02 +0000

Dr James Thaventhiran points to a diagram of a 14-year-old boy’s family tree. Some of the symbols are shaded black.

“These family members have a very severe form of immunodeficiency. ̽��ֱ��children get infections and chest problems, the adults have bowel problems, and the father died from cancer during the study. ̽��ֱ��boy himself had a donor bone marrow transplant when he was a teenager, but he remains very unwell, with limited treatment options.”

To understand the cause of the immunodeficiency, Thaventhiran, a clinical immunologist in Cambridge’s Department of Medicine, has been working with colleagues at the Great Northern Children’s Hospital in Newcastle, where the family is being treated.

Theirs is a rare disease, which means the condition affects fewer than 1 in 2,000 people. Most rare diseases are caused by a defect in the genetic blueprint that carries the instruction manual for life. Sometimes the mistake can be as small as a single letter in the three billion letters that make up the genome, yet it can have devastating consequences.

When Thaventhiran and colleagues at the National Institute for Health Research (NIHR) BioResource in Cambridge carried out whole genome sequencing on the boy’s DNA, they discovered a defect that could explain the immunodeficiency. “We believe that just one wrong letter causes a malfunction in an immune cell called a dendritic cell, which is needed to detect infections and cancerous cells.”

Now, hope for an eventual cure for family members affected by the faulty gene is taking shape in the form of ‘molecular scissors’ called CRISPR-Cas9. Discovered in bacteria, the CRISPR-Cas9 system is part of the armoury that bacteria use to protect themselves from the harmful effects of viruses. Today it is being co-opted by scientists worldwide as a way of removing and replacing gene defects.

One part of the CRISPR-Cas9 system acts like a GPS locator that can be programmed to go to an exact place in the genome. ̽��ֱ��other part – the ‘molecular scissors’ – cuts both strands of the faulty DNA and replaces it with DNA that doesn’t have the defect.

“It’s like rewriting DNA with precision,” explains Dr Alasdair Russell. “Unlike other forms of gene therapy, in which cells are given a new working gene but without being able to direct where it ends up in the genome, this technology changes just the faulty gene. It’s precise and it’s ‘scarless’ in that no evidence of the therapy is left within the repaired genome.”

Russell heads up a specialised team in the Cancer Research UK Cambridge Institute to provide a centralised hub for state-of-the-art genome-editing technologies.

“By concentrating skills in one area, it means scientists in different labs don’t reinvent the wheel each time and can keep pace with the field,” he explains. “At full capacity, we aim to be capable of running up to 30 gene-editing projects in parallel.

“What I find amazing about the technology is that it’s tearing down traditional barriers between different disciplines, allowing us to collaborate with clinicians, synthetic biologists, physicists, engineers, computational analysts and industry, on a global scale. ̽��ֱ��technology gives you the opportunity to innovate, rather than imitate. I tell my wife I sometimes feel like Q in James Bond and she laughs.”

Russell’s team is using the technology both to understand disease and to treat it. Together with Cambridge spin-out DefiniGEN, they are rewriting the DNA of a very special type of cell called an induced pluripotent stem cell (iPSC). These are cells that are taken from the skin of a patient and ‘reprogrammed’ to act like one of the body’s stem cells, which have the capacity to develop into almost any other cell of the body.

In this case, they are turning the boy’s skin cells into iPSCs, using CRISPR-Cas9 to correct the defect, and then allowing these corrected cells to develop into the cell type that is affected by the disease – the dendritic cell. “It’s a patient-specific model of the cure in a Petri dish,” says Russell.

̽��ֱ��boy’s family members are among a handful of patients worldwide who are reported to have the same condition and among around 3,500 in the UK who have similar types of immunodeficiency caused by other gene defects. With such a rare group of diseases, explains Thaventhiran, it’s important to locate other patients to increase the chance of understanding what happens and how to treat it.

He and Professor Ken Smith in the Department of Medicine lead a programme to find, research and provide diagnostic services to these patients. So far, 2,000 patients (around 60% of the total affected in the UK) have been recruited and sequenced by the NIHR Bioresource, making it the largest worldwide cohort of patients with primary immunodeficiency."

“We’ve now made 12 iPSC lines from different patients with immunodeficiency,” adds Thaventhiran, who has started a programme for gene editing all of the lines. “This means that for the first time we’ll be able to investigate whether correcting the mutation corrects the defect – it’ll open up new avenues of research into the mechanisms underlying these diseases.”

But it’s the possibility of using the gene-edited cells to cure patients that excites Thaventhiran and Russell. They explain that one option might be to give a patient repeated treatments of their own gene-edited iPSCs. Another would be to take the patient’s blood stem cells, edit them and then return them to the patient.

̽��ֱ��researchers are quick to point out that although the technologies are converging on this possibility of truly personalised medicine, there are still many issues to consider in the fields of ethics, regulation and law.

Dr Kathy Liddell, who leads the Cambridge Centre for Law, Medicine and Life Sciences, agrees: “It’s easy to see the appeal of using gene editing to help patients with serious illnesses. However, new techniques could be used for many purposes, some of which are contentious. For example, the same technique that edits a disease in a child could be applied to an embryo to stop a disease being inherited, or to ‘design’ babies. This raises concerns about eugenics.

“ ̽��ֱ��challenge is to find systems of governance that facilitate important purposes, while limiting, and preferably preventing, unethical purposes. It’s actually very difficult. Rules not only have to be designed, but implemented and enforced. Meanwhile, powerful social drivers push hard against ethical boundaries, and scientific information and ideas travel easily – often too easily – across national borders to unregulated states.”

A further challenge is the business case for carrying out these types of treatments, which are potentially curative but are costly and benefit few patients. One reason why rare diseases are also known as orphan diseases is because in the past they have rarely been adopted by drug companies.

Liddell adds: “CRISPR-Cas9 patent wars are just warming up, demonstrating some of the economic issues at stake. Two US institutions are vigorously prosecuting their own patents, and trying to overturn the others. There will also be cross-licensing battles to follow.”

“ ̽��ֱ��obvious place to start is by correcting diseases caused by just one gene; however, the technology allows us to scale up to several genes, making it something that could benefit many, many different diseases,” adds Russell. “At the moment, the field as a whole is focused on ensuring the technology is safe before it moves into the clinic. But the advantage of it being cheap, precise and scalable should make CRISPR attractive to industry.”

In ten years or so, speculates Russell, we might see bedside ‘CRISPR on a chip’ devices that screen for mutations and ‘edit on the fly’. “I’m really excited by the frontierness of it all,” says Russell. “We feel that we’re right on the precipice of a new personalised medical future.”

Gene editing using ‘molecular scissors’ that snip out and replace faulty DNA could provide an almost unimaginable future for some patients: a complete cure. Cambridge researchers are working towards making the technology cheap and safe, as well as examining the ethical and legal issues surrounding one of the most exciting medical advances of recent times.

I’m really excited by the frontierness of it all. We feel that we’re right on the precipice of a new personalised medical future.

Alasdair Russell

̽��ֱ��District

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

Yes

Algorithm matches genetic variation to disease symptoms and could improve diagnosis of rare diseases

cjb250 — Wed, 19 Apr 2017 11:01:20 +0000

Around 80% of rare diseases are thought to have a genetic component, but currently many patients experience long delays in diagnosis or never receive a diagnosis at all. Recent developments in our ability to obtain whole or partial genome sequences cheaply and efficiently now makes it feasible for patients to benefit from this technology through cheaper, faster diagnosis of disease, and the development of new therapies. Many international projects are currently seeking to capitalise on these developments by sequencing hundreds of thousands of individuals, such as the UK 100,000 Genome Project. However, a major challenge remains how to associate changes in a patient’s DNA to their disease.

“ ̽��ֱ��challenge for scientists is to identify which of the hundreds of thousands of genetic differences between a patient and an unaffected individual might be responsible for their disease,” says Dr Paul Schofield from the Department of Physiology, Development and Neuroscience at the ̽��ֱ�� of Cambridge. “Given the huge complexity of this problem, it has been described as ‘looking for needles in stacks of needles’.”

Now, Dr Schofield and a team of researchers from the UK and Saudi Arabia have developed an algorithm, published this week in the journal PLOS Computational Biology, that can identify variants that modify the normal function of a gene associated with a particular disease.

A framework developed by the team, called PhenomeNET, matches a patient’s phenotype (symptoms) to a large database of gene-to-phenotype associations, including those from studies involving mice and zebrafish, in order to identify disease-causing genes.

Mice and zebrafish are commonly used when studying the biology underlying human diseases as they have a number of important genetic and biological similarities to us. For many years, data on the consequences of naturally-occurring and experimentally-induced genetic variants in these animal models have been collected resulting in a huge ‘Big Data’ resource associating genetic makeup and phenotype, such as the Mouse Genome Database, which contains more than 60,000 of these associations.

By combining PhenomeNET with methods that find harmful variants in a genomic sequence, the team developed the PhenomeNET Variant Predictor (PVP) system, an algorithm that prioritises these variants with their likelihood of involvement in human disease.

“Our algorithm makes use of clinical and experimental data that have been collected for years and uses them to identify the genetic variants underlying the conditions of patients with genetic disorders,” adds Professor Robert Hoehndorf from King Abdullah ̽��ֱ�� of Science and Technology (KAUST) in Saudi Arabia.

Working with Dr Nadia Schoenmakers at the Wellcome Trust-Medical Research Council Institute of Metabolic Science in Cambridge, the team was able to show that the new algorithm can identify genetic changes in patients with congenital thyroid disease, and can reveal candidate genetic changes in ‘Mendelian’ diseases where only a single gene is involved.

“We’ve shown that our algorithm works for simpler diseases and now the real test will be to determine whether a similar approach can be applied to complex diseases, such as diabetes, where multiple genes are involved,” says Professor George Gkoutos from the ̽��ֱ�� of Birmingham.

Reference
Boudellioua I, Mahamad Razali RB, Kulmanov M, Hashish Y, Bajic VB, et al. Semantic prioritization of novel causative genomic variants. PLOS Comp Biol; 17 April 2017; DOI: 10.1371/journal.pcbi.1005500

A faster and more accurate method of identifying which of an individual’s genes are associated with particular symptoms has been developed by a team of researchers from the UK and Saudi Arabia. This new approach could enable scientists to take advantage of recent developments in genome sequencing to improve diagnosis and potential treatment options.

̽��ֱ��challenge for scientists is to identify which of the hundreds of thousands of genetic differences between a patient and an unaffected individual might be responsible for their disease

Paul Schofield

greyloch

Human Genome mannequin

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

Yes

Licence type:

Attribution-ShareAlike

̽��ֱ��Big Dating Game

cjb250 — Tue, 09 Jun 2015 11:25:51 +0000

At some point in their career, every doctor will encounter a patient whose condition perplexes them, requiring detailed investigation and discussion with colleagues before diagnosis is possible. After all, not every disease is as common as cancer, which affects around one in three of us, or depression, which affects one in 10.

Dr Lucy Raymond from the Department of Medical Genetics specialises in rare diseases. Technically, this means diseases that affect fewer than one in 2,000 people, but in fact, Raymond sees children with learning disabilities so rare that they may be the only person in the UK to be affected.

These conditions are usually caused by one of two scenarios: a spontaneous change to their DNA, not inherited, or a ‘recessive disorder’ where two copies of the same, rare variant are necessary for the disease and each parent unwittingly passes on a copy. Comparing the child’s and their parents’ genomes enables the researchers to pinpoint the gene responsible. In extremely rare cases – where the patient appears to be truly unique – the researchers need to study whether the same variant in mice or zebrafish creates a similar condition.

“Or,” Raymond explains, “we might essentially generate a ‘dating agency’ to try to match our patient with a similar case somewhere else in the world.” With these diseases as rare as they are, the only way for this to be viable would be to have access to tens, possibly hundreds, of thousands of potential matches: something the era of ‘big data’ makes possible.

But this presents a potential problem: how to share information about the patient without breaking their confidentiality. Unlike in the USA, where projects such as the Broad Institute’s Exome Aggregation Consortium (ExAC) place genome data in the public domain, data in the UK is deposited in a ‘managed-access’ database: bona fide researchers with a clear research proposal are allowed access, and only then after signing a commitment saying they will not attempt to identify individual patients.

“We have to remember that big data is great, but it isn’t our data: it’s people’s data and we need to be respectful of this. People in the UK are often altruistic; we have free blood donation, we have a tremendous tradition of patients giving to help others. We must not jeopardise this relationship.

“Parents know that even if finding the gene abnormality that is responsible will not immediately help their child, it may help ensure that others don’t have to wait 20 years before their child receives a diagnosis. They’re happy to share the data on that basis, but are less keen on the idea that they’ll lose control of the information.”

For several years, Raymond, Professor Willem Ouwehand and Dr John Bradley have been leading the National Institute for Health Research BioResource for Rare Diseases in Cambridge, which has recruited some 5,800 patients. They are now part of a major initiative launched by Prime Minister David Cameron: the 100,000 Genomes Project. Cambridge ̽��ֱ�� Hospitals NHS Foundation Trust will lead the East of England Genomic Medicine Centre, one of 11 centres across the UK aimed at realising this project and sequencing the genomes of patients affected by cancer or rare diseases.

“ ̽��ֱ��100,000 Genomes Project is about going forward to having a truly national health service, not a provincial, regional health service,” explains Raymond. “ ̽��ֱ��data will be central, will be national, will be available to researchers and healthcare professionals across the country.”

̽��ֱ��sheer number of people recruited will create a powerful dataset and ensure that clinicians and researchers don’t have to start from scratch each time they encounter a new case. In fact, the value of a patient’s genome extends beyond just helping identify the cause of their disease: it’s also important as a ‘control’ to compare against and help find the cause of another patient’s disease. “It’s a form of ‘enforced altruism’. Having all the data stored in a central place means that everybody’s data acts as a control for everybody else’s. It has a multiplying effect.”

Big data also reveals an otherwise glaringly obvious fact that the name ‘rare diseases’ obscures: one in 2,000, even in a population of 64 million, is not an insignificant number of people. “Ten years ago people used to ask ‘Why study rare diseases when they’re so rare?’ It’s only recently that people are coming round to see that, with big data, rare is common.

“Rare diseases are becoming increasingly tractable, too, so now there’s a huge interest in them, which is good: it’s not your fault if your disease is rare. Solving these problems is the next big challenge,” says Raymond with a glint in her eye. “If it was all easy, we wouldn’t be doing it – in typical Cambridge style.”

When is a rare disease not a rare disease? ̽��ֱ��answer: when big data gets involved. An ambitious new research project aims to show patients that they are not alone.

We might essentially generate a ‘dating agency’ to try to match our patient with a similar case somewhere else in the world

Lucy Raymond

Duncan Hull

DNA/protein function finder from the Wellcome Trust, Sanger Institute, emblebi and YourGenome

Trust me, I’m an e-doctor

Big data ‘dating agencies’ are not just for people with rare conditions. A similar concept could help patients with far more common conditions receive the best possible hospital treatment.

Addenbrooke’s Hospital in Cambridge is one of the first ‘eHospitals’ in England, explains Dr Lydia Drumright from the Department of Medicine. Everything that happens to you within the hospital – every test result, every diagnosis, every drug prescribed – is captured in an electronic record. Drumright and her colleague Dr Afzal Chaudhry believe that the wealth of information in these records can be used to better inform the treatments of individuals.

“Around 10–20% of our patients may have diabetes or acute kidney injury, but that’s not necessarily why they’re here,” explains Drumright. “They might have had a heart attack, so they’re being cared for by the cardiology team, but the drugs they’re prescribed might have an impact on their other conditions. Added to that, they’re now more susceptible to infection.

“It’s the junior doctors that have to look after the patients and do the basic prescribing. They’re still learning, but need to know which drugs work best and the hospital’s policy for prescribing antibiotics.”

Could a patient ‘dating agency’ not dissimilar to that suggested by Raymond, based on everyone’s medical records, help these junior doctors? “ ̽��ֱ��doctor can search for other patients that look like their own. They can go back historically and see what drugs were prescribed and what their outcomes looked like.”

Drumright is mindful of setting up a system that tells doctors what to prescribe; the literature about how we interface with technology suggests that people can too easily surrender their responsibility. Instead, it’s about building on collective knowledge, “What we’re trying to do is enhance the doctor’s experience so that it’s not ‘my experience as me’, it’s the experience of every prescriber in the hospital.”

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

Yes

Licence type:

Attribution