The  findings of the University of Oxford led study, published in , are an exciting first step towards the development of future  treatments for the disorders which have devastating impacts on learning, behaviour, speech, and movement.

While most NDDs are thought to be genetic and caused by changes to DNA, to date around 60% of individuals with the conditions do not know the specific DNA change that causes their disorder.

Nearly all genes known to be involved in NDD are responsible for making proteins. However the team discovered that the gene RNU4-2 instead makes an RNA molecule that plays an important role in how other genes are processed in cells.

The study estimates that these specific changes in the RNU4-2 gene can explain 0.4% of all NDD cases globally, potentially impacting hundreds of thousands of families across the world.

While previous studies have only looked at genes that make proteins, data from the , used by the team meant they could sequence entire genomes enabling changes in genes that don鈥檛 make proteins, like RNU4-2, to be analysed as well.

The study was led by Nicola Whiffin, Associate Professor at the Big Data Institute and Centre for Human Genetics at the University of Oxford.

The team found mutations in RNU4-2 in 115 people with NDDs, many of whom had the exact same variant which adds a single extra base at an important position in the RNA.

The second haJamie Ellingford is  Senior Research Fellow at Swag直播 and Lead Genomics Data Scientist at Genomics England

He said: 鈥淭his is a really powerful discovery which shows just how far we have developed as a global scientific and clinical community.

鈥淚t provides evidence of how we now have the capability to pinpoint all types of differences in people's DNA which can be drivers of disease, and can rapidly connect families and researchers from across the world.

鈥淪wag直播 has an excellent track record at the cutting edge of human genomics research and the discovery of new types of diseases.

This finding builds upon jointly led work at the University of Swag直播 and the University of Oxford to understand the impact of DNA differences in the part of the human genome that doesn't directly encode for protein, once called "junk DNA" because of its unknown role.

鈥淭he close alliances between computational science, genomics and clinical discovery at Swag直播 will hopefully enable future discoveries like this that help families and other researchers better understand genomic diseases."

Nicole Cedor, mother to 10-year-old Mia Joy, said: 鈥淲hen Undiagnosed Network told us about three years ago that there was nothing else they could do, we resigned ourselves to the fact that we may never find out.

鈥淪o, you can imagine our shock to get this news. With the information we have gained, we are getting blood work to check iron levels, getting a DEXA bone scan next week, and we have a referral in for endocrinology.鈥�

鈥淲e are so grateful to each person on the research teams that worked tirelessly to find this diagnosis.  It is one thing to write papers and crunch all that data, then another to see a family with a precious unique child who is living it day by day.  This where the data meets real life. We like to refer to RNU4-2 as "renew", as our family is being renewed by this new information and hope for the future.鈥漧f goes here.

Professor Whiffin said: 鈥淲hat is most remarkable about this discovery is how often changes in this gene result in NDD. Most protein-coding genes involved in NDD are thousands of DNA bases long. RNU4-2 is around 50 times smaller but changes in this gene are almost as frequent a cause of NDD as these protein-coding genes. Including RNU4-2 in standard clinical genetic testing will end diagnostic odysseys for thousands of NDD patients worldwide and provide long-awaited hope to families.鈥�

The news offers hope that doctors may one day be able to investigate suspected kidney pathologies without carrying out invasive procedures such as biopsies, raising the tantalising prospect of earlier and simpler disease detection.

The impact of late detection of kidney disease can be severe and can lead to serious - and sometimes life threatening - complications.

The team led by University of Swag直播 scientists measured the levels of approximately 20,000 genes in each cellular sediment sample of urine using a technique called transcriptomics.

The British Heart Foundation-funded study benefited from access to the world's largest collection of human kidney samples collected after surgery or kidney biopsy conducted before transplantation, known as the Human Kidney Tissue Resource, at Swag直播.

They extracted both DNA and RNA from each sample and connected information from their analysis, together with data from previous large-scale analyses of blood pressure (called genome-wide association studies), using sophisticated computational methods.

Transcriptomics allows scientists to understand which genes are turned on or off in different situations so they can understand how cells respond to changes in their environment.

Such molecular-level understanding enhances the precision and effectiveness of diagnostic approaches, potentially improving patient care and outcomes.

The study, published in Nature Communications today (19/03/24) also showed that low levels of a specific gene in the kidney is likely to be one of the causes of high blood pressure.

The gene, called ENPEP, is an important part of the hormonal system which is essential for regulation of blood pressure, by making an enzyme called aminopeptidase A.

It was one of 399 genes identified by the researchers whose levels in the kidney are also causally related to either increasing or decreasing in blood pressure.

The study was led by Chair of Cardiovascular Medicine at Swag直播 and Honorary Consultant Physician at Swag直播 University NHS Foundation Trust.

He is also Integrative Cardiovascular Medicine Co-Theme Lead at the National Institute for Health and Care Research (NIHR) Swag直播 Biomedical Research Centre (BRC), which supported the research.

He said: 鈥淭his study shows that using cutting-edge technology we are able to combine different unique datasets together using genetics as a connector.

鈥淥ne of the most exciting findings of that is we discover how cells harvested from urine have the potential to provide a glimpse into the molecular operation of the human kidney.

鈥淭hat gives us an exciting avenue of research for non-invasive diagnostic testing.鈥�

He added: 鈥淧ersistent high blood pressure鈥攐r hypertension鈥攃an increase the risk of a number of serious and potentially life-threatening health conditions, such as heart disease, heart attacks and strokes.

鈥淥ur results also show that the gene ENPEP in the kidney is a new promising target for development of new blood pressure lowering medications.

鈥淭here are several classes of effective antihypertensives available, though the last new medication approved for management of high blood pressure was over a decade and a half ago.

鈥淲hile for some people, they are effective, side effects make it difficult for others to take over the long term. That is why we need more choice.鈥�

Professor Bryan Williams, Chief Scientific and Medical Officer at the British Heart Foundation, said: 鈥淭here is a well-known link between the heart and the kidneys in regulating blood pressure. This study uses cutting-edge scientific techniques to analyse genes present in kidney cells that are normally expelled in the urine. Analysing these cells could reveal which genes may be playing a key role in people with high blood pressure, and could potentially offer clinicians a new, non-invasive way to help diagnose those with kidney disease early on.

鈥淗igh blood pressure is a major risk factor for heart disease and stroke, and this research has identified a gene called ENPEP that regulates important enzymes in the kidney that could be a promising target for blood pressure-lowering drugs. This study has demonstrated the power in using large sets of data and in doing so, shows how funding research like this can help us to improve treatment for people with high blood pressure.鈥�

The paper Genetic imputation of kidney transcriptome, proteome and multi-omics illuminates  new blood pressure and hypertension targets  is available . The DOI for the paper is 10.1038/s41467-024-46132-y

The study potentially paves the way for genetically determined predictors of disease complications to allow earlier interventions.

Published in , the study co-led by Professor Andrew Morris from Swag直播 is a collaboration of more than 350 authors from 130 studies around the world and the largest type 2 diabetes genome-wide association study to date.

The researchers scanned complete sets of DNA (genomes) from 2.5 million people 鈥� a sample size almost three times larger than in previous studies 鈥� to identify variations in the genetic sequence associated with the development and progression of type 2 diabetes.

More than 400 million people worldwide are living with type 2 diabetes, a condition which occurs when the body is not able to make enough of the hormone insulin, causing the level of sugar in the blood to become too high.

Left untreated, high blood sugar levels can cause serious health problems and complications that affect  the eyes, kidney and nerves. People with type 2 diabetes are also more likely to suffer from heart disease and stroke.

As well as factors such as weight and exercise, the risk of developing type 2 diabetes, which is the most common type of diabetes, is also linked to genetics. Variations of the genetic code can increase the risk of developing type 2 diabetes and its complications, which can be passed down through families.

The research team revealed over 600 places in the genome -  a biological blueprint needed for life to exist - which increase the risk of type 2 diabetes, of which 145 had previously been unidentified.

The DNA of more than 2.5 million people were analysed, including 428,452 people who have type 2 diabetes from six different ancestry groups: African American, East Asian, European, Hispanic, South African and South Asian.

Studying a range of ancestry groups ensures that the findings of the research are relevant to diverse populations across the globe, where type 2 diabetes is a major health concern.

For the first time across multiple ancestry groups, the team were also able to generate genetic risk scores associated with developing harmful type 2 diabetes complications such as coronary artery disease and diabetic kidney disease.

Senior co-corresponding author Professor Andrew Morris, Professor of Statistical Genetics at Swag直播 and the (NIHR) (BRC), said:

鈥淥ur work has improved our knowledge of the biological processes that lead to the development of type 2 diabetes and progression to its complications in diverse population groups across the world.

鈥淏etter understanding of the genetic causes of the disease has the potential to allow us to predict these complications before they occur and may help put in place early interventions to delay or even prevent these debilitating medical conditions."

Five children under one year of age with the condition also known as mucopolysaccharidosis type II (MPS II) will be treated with autologous hematopoietic stem cell (HSC) gene therapy.

The children will continue to receive enzyme replacement therapy during treatment, but once the gene therapy begins to work, the research team say part of the trial aims to remove the need for weekly enzyme replacement therapy over the child鈥檚 lifetime, while the other aim is to safely target the brain disease suffered by these patients.

The combined phase 1 and 2 clinical trial initiated by University of Swag直播 researchers, is now open to recruitment. AVROBIO, the previous funders of the program, have returned the license to Swag直播.

The study will be carried out at Royal Swag直播 Children鈥檚 Hospital (RMCH) in collaboration with the Swag直播 Centre for Genomic Medicine at Saint Mary鈥檚 Hospital 鈥� both part of Swag直播 University NHS Foundation Trust (MFT), will trial the drug for the treatment for this rare inherited disorder, which was developed over eight years by Brian Bigger, Professor of Cell and Gene Therapy at Swag直播.

Professor Bigger and his team this month published a in Molecular Therapy clinical Methods which validates the proof-of-concept outcomes findings in mice, providing further long-term efficacy data.

The trial aims to recruit up to five patients with severe MPS II who are aged between 3 months and 12 months at time of consent. Inclusion criteria are for children in the above age range with a confirmed diagnosis of severe MPSII who may already be on enzyme replacement therapy but have not yet developmentally declined.

It will be a 24-month, single-arm, open label study which will evaluate the HSC gene therapy鈥檚 safety and tolerability, as well as its pharmacodynamic and clinical efficacy.

Children with severe Hunter syndrome cannot properly break down complex sugar molecules and have widespread symptoms including rapid and progressive learning and memory problems, heart and lung dysfunction, hyperactivity and behavioural problems, bone and joint malformations and hearing impairment.

The UK Medicines and Healthcare Products Regulatory Agency (MHRA), Research Ethics Committee (REC), and Health Research Authority (HRA) have all approved the clinical trial application that was submitted by Swag直播 in August 2022.

The clinical trial will be led by Professor Rob Wynn, Consultant Paediatric Haematologist at RMCH, together with Professor Simon Jones, Consultant in Paediatric Inherited Metabolic Disease at Saint Mary鈥檚 Hospital, and Professor Bigger at Swag直播. Swag直播 will act as trial sponsor.

Children with Hunter syndrome have a missing gene, meaning they cannot produce an important enzyme called iduronate-2-sulfatase or IDS. The gene therapy works by collecting HSCs from the patient and inserting a working copy of the gene into the HSCs using a lentiviral gene therapy vector. The modified HSCs are then infused back into the patient to engraft in the bone marrow. Following successful engraftment of modified HSCs in the bone marrow, these cells start to produce daughter blood cells which contain the IDS gene and enzyme which are distributed throughout the body, including the brain.

 Professor Bigger said: 鈥淭his is a next generation stem cell gene therapy approach, which allows transit of the IDS enzyme into the brain. The newly inserted IDS gene produces an IDS enzyme that contains a proprietary ApoEII-tagged sequence, which can bind to ApoE-dependent receptors on the blood brain barrier, and move enzyme into the brain more efficiently, thus potentially normalizing brain pathology.

鈥淭his should speed up delivery of enzyme to the brain, where it is most needed as we can leverage all the enzyme produced by the blood to do this rather than just relying on the engraftment of monocyte cells from the blood into the brain.鈥�

He added: 鈥淲e鈥檙e very excited by the pre-clinical studies we carried out in mice, which showed the potential to correct disease in the body and normalize brain pathology.

鈥淢ice with Hunter syndrome treated with the HSC gene therapy showed dramatic improvement in their condition, including normalization of working memory problems, and skeletal features such as the cheekbone dimensions and the width of the humerus and femur bones.鈥�

The trial is the culmination of a more than 15-year collaborative effort with Professor Wynn and Professor Jones at MFT to develop HSC gene therapies for neurological lysosomal disorders and is now the second potential neurological gene therapy that this collaborative team has brought into the clinical setting.

Bob Stevens, chief executive of the MPS society said: 鈥淭his ground-breaking trial initiated by Swag直播 offers the possibility of new treatment options in the future for patients with the severest form of MPSII Hunters. We look forward to hearing the outcome of this trial, with cautious optimism and hope that science will offer the chance of a 鈥楻are Life Lived Better鈥�.鈥�

The award - which includes University of Swag直播 researchers - will ensure the study鈥檚 long-term sustainability to fight health inequality in an underrepresented population of British South Asians. Launched in 2014, the community-focused project has recruited over 55,000 volunteers across London, Bradford, and Swag直播.

Genes & Health brings together internationally renowned scientists to make new discoveries, using cutting-edge techniques such as discovering 鈥榢nockout genes,鈥� developing polygenic risk scores, and helping with the design of new drug treatments.

The funding will allow Genes & Health to continue to provide a unique data source for researchers, generate valuable long-term data, as well as expand its focus on two areas of unmet health needs: mental health and pregnancy.

Studies have shown that individuals belonging to South Asian communities are comparatively less likely to receive diagnosis for mental health conditions, such as depression. As part of its aim to improve the lives of South Asians, Genes & Health will develop and deliver an innovative online platform that will be used to generate large-scale mental health research.

Similarly, British South Asian women face greater risks for disorders such as gestational diabetes and pre-eclampsia compared to the general population during and after pregnancy.

The inclusion of this pregnancy cohort within Genes & Health will enable a greater understanding of pregnancy-associated medical disorders and prediction of long-term health risks following illness.

Dr Sarah Finer, Principal Investigator of the new award said: 

鈥淲e are excited to receive funding to expand Genes & Health over the coming years and continue to make critical scientific discoveries that help improve the health of British Bangladeshis and British Pakistanis.鈥�

Councillor Ahsan Khan, Chair of the Genes & Health Community Advisory Group said: 

鈥淕enes & Health has received incredible support from our volunteers and partners in the NHS, community organisations and local government. We look forward to another five years of work in these fantastic partnerships.鈥� 

•  Want to join the Genes & Health  programme and make a meaningful contribution to scientific advancements in health and disease research? Visit us at  and be part of shaping the future of medical research.
• Find out more about Genes & Health鈥檚 pioneering research through the Queen Mary, University of London Research Highways feature here:

Matthew Cobb, from Swag直播 and  Nathaniel Comfort from the John Hopkins University School of Medicine make the case for the scientist in a comment article in this week鈥檚 .

The seminal paper by James Watson and Francis Crick on the discovery of the DNA double helix was published in Nature 70 years ago this week.

Many believe the eureka moment came when Watson was shown an X-ray image of DNA taken by Franklin, without her permission or knowledge.

Known as Photograph 51, the image is treated as 鈥渢he philosopher鈥檚 stone of molecular biology鈥�, write Cobb and Comfort. 鈥淚t has become the emblem of both Franklin鈥檚 achievement and her mistreatment,鈥� they explain.

n this version of events, Franklin is portrayed as a brilliant scientist, but one who was ultimately unable to decipher what her own data were telling her about DNA. She supposedly sat on the image for months without realizing its significance, only for Watson to understand it at a glance.

But when visiting Franklin鈥檚 archive at Churchill College in Cambridge, the authors found a hitherto unstudied draft news article 鈥� written by journalist Joan Bruce in consultation with Franklin and meant for publication in Time magazine 鈥� as well as an overlooked letter from one of Franklin鈥檚 colleagues to Crick.

Together, she documents show that Franklin did not fail to understand the structure of DNA. Cobb and Comfort argue that Franklin was 鈥渁n equal member of a quartet who solved the double helix鈥�. Along with Maurice Wilkins, she was 鈥渙ne half of the team that articulated the scientific question, took important early steps towards a solution, provided crucial data and verified the result鈥�.

Getting Franklin鈥檚 story right is crucial, write Cobb and Comfort. 鈥淪he was up against not just the routine sexism of the day, but also more subtle forms embedded in science 鈥� some of which are still present today.鈥�

The study was funded by Orchard Therapeutics, sponsored by Swag直播 and conducted at Swag直播 University NHS Foundation Trust.

It found four out of five patients diagnosed with Sanfilippo have continued to gain cognitive skills in line with development in healthy children after being given the investigational gene therapy, OTL-201.

However, the researchers urge caution as the majority of patients have not reached the age of 4-5 years where the most severe stages of disease progression typically present.

The trial patients were 6 to 24 months of age at the time of administration of OTL-201, and the preliminary results are based on a median follow-up of 2 years (range: 9-30 months).

Patients enrolled in the trial will be followed for a minimum of 36 months during which time the study investigators will continue to report additional biochemical and clinical outcomes.

The rare genetic metabolism disorder called Sanfilippo syndrome Type A- or Mucopolysaccharidosis Type IIIA (MPS-IIIA)- is a genetic disease with devastating effects on the central nervous system affecting around 1 in 70,000 children.

Patients with MPS-IIIA have a mutation in the SGSH gene, causing them to lack an enzyme which normally breaks down large sugar molecules.

These molecules then accumulate in the cells of the body causing irreparable damage to many organs including the brain, leading to inflammation and damage to brain tissue.

The investigational gene therapy OTL-201 works by collecting a patient鈥檚 own blood stem cells and inserting a working copy of the SGSH gene using a modified virus, known as a lentiviral vector.

The patient鈥檚 modified blood stem cells, now including a working copy of the SGSH gene, are then given back to the patient.

This enables patients to then make this missing SGSH enzyme and provide it throughout the body from blood cells made in the bone marrow. These stem cells can make monocytes, which are specialised blood cells able to enter the brain. This means they can release SGSH enzyme to potentially help stop damage to the brain.

The results showed:

• An improvement in neurocognitive assessments compared with natural progression of the disease in one of the children at 18-months post-treatment.
• Three additional patients are currently within the normal cognitive development range at 9 to 18 months post-treatment, but require longer follow-up to assess outcomes.
• After a median of two years, OTL-201 which was generally well tolerated in all the patients, achieved sustained engraftment in the bone marrow.
• Higher amounts of the SGSH enzyme were seen than would be normally found in the blood and cerebrospinal fluid of healthy children.

Six serious adverse events (SAEs) have been reported in patients in the study and were considered to be caused by procedures required for the administration of OTL-201 or background disease. No SAEs were considered related to OTL-201 and no fatal cases have been reported, to date.

Professor Brian Bigger, Chair in Cell and Gene Therapy at the University of Swag直播, who carried out the preclinical work said: 鈥淲e have been hopeful this therapy will be transformative for patients- and these early results are very encouraging - but there鈥檚 still a long way to go.鈥�

鈥淚mportantly, the safety profile of the investigational therapy is currently considered favourable in these patients, with the lentiviral vector reporting a polyclonal pattern of integration, and blood stem cells engrafting and producing cells in the blood system which are able to make the missing enzyme in patients.

鈥淭he human monocyte-specific promoter in the lentiviral vector was designed to have a very low risk of causing insertional mutagenesis - the accidental switching on of genes causing cancer. This is critical for the future safety of the patients and the developmental potential of this therapy.鈥�

Professor Robert Wynn, Chief Investigator on the trial at The Royal Swag直播 Children鈥檚 Hospital, part of Swag直播 University NHS Foundation Trust (MFT) said: 鈥淭hese are encouraging results for children living with MPS-IIIA and their families, who currently have no effective treatment options.鈥�

鈥淚n addition to sustained engraftment of gene-corrected cells and supraphysiological SGSH enzyme levels in the periphery, the early neurocognitive findings show most patients are gaining skills in line with the development of healthy children. In one patient, we also have seen a marked improvement from disease natural history, and we hope to see similar results in the other patients with longer follow-up.鈥�

Professor Simon Jones, Consultant in Paediatric Inherited Metabolic Disease at the Swag直播 Centre for Genomic Medicine at Saint Mary鈥檚 Hospital and Clinical Director of NIHR Swag直播 Clinical Research Facility at Royal Swag直播 Children鈥檚 Hospital, said: 鈥淭here are currently no other treatment options for children with MPS-IIIA. We hope this therapy will have a positive impact on the lives of our children and their families, improving the symptoms of this devastating disease.鈥�

Leslie Meltzer, Ph.D., chief medical officer of Orchard Therapeutics said: 鈥淭hese promising early findings continue to show the ability of our HSC gene therapy platform to enable the migration of gene-corrected cells into the central nervous system and the localized delivery of therapeutic enzymes and proteins to the brain to potentially correct neurodegeneration in multiple severe conditions, building on our programs in neurometabolic disorders.鈥�

鈥淲hile these early results are encouraging, longer follow up is needed, as the majority of the patients in this trial have not reached the age where the most severe stages of disease progression typically manifest. We are working with our collaborators at Swag直播 and Royal Swag直播 Children鈥檚 Hospital to continue following patients in this ongoing study and more fully characterize the clinical and safety profile of OTL-201.鈥�

The results were presented at the WORLD 鈩�2023 on Lysosomal Diseases on 24/02/23.

Swag直播 researchers, based at Saint Mary鈥檚 Hospital, part of Swag直播 University NHS Foundation Trust (MFT), worked with Swag直播 and Swag直播-based firm genedrive Plc on the Pharmacogenetics to Avoid Loss of Hearing (PALOH) study. Together, they developed the pioneering, rapid bedside genetic test which was .

Using a cheek swab, the test can identify in 26 minutes whether a critically ill baby admitted to intensive care has a gene change that could result in permanent hearing loss if they are treated with a common emergency antibiotic, Gentamicin.

While Gentamicin is used to safely treat approximately 100,000 babies a year, one in 500 babies carry the gene change that can lead to permanent hearing loss when given the antibiotic.

The new test means that babies found to have the genetic variant can be given an alternative antibiotic within the 鈥榞olden hour鈥� and could save the hearing of 200 babies in England every year.

PALOH study lead, Professor Bill Newman, Consultant in Genomic Medicine at MFT and Professor of Translational Genomic Medicine at Swag直播, said: 鈥淚 am delighted for the team to receive this recognition of their fantastic efforts and their innovative approach in bringing this test to fruition.鈥�

The new swab test technique, which was piloted at MFT, replaces a test that traditionally took several days and is the first use of a rapid point of care genetic test in acute neonatal care.

Dr Ajit Mahaveer, Consultant Neonatologist, Rachel James, Senior Research Coordinator and Nicola Booth, Research Nurse Manager on the Newborn Intensive Care Unit at Saint Mary鈥檚 Hospital, attended the awards ceremony in London and accepted the award on behalf of the team.

Dr Mahaveer said: "I am incredibly proud to be part of the team who made this study a reality and to be recognised at this year鈥檚 New Statesman Positive Impact Awards. It鈥檚 an honour to accept the award on behalf of the team, knowing the work we have put into delivering this research will truly make a difference to hundreds of babies鈥� lives each year.

鈥淎s a doctor dealing daily with infection, my main concern was how easy and quickly the test was to conduct, as it鈥檚 important that we do not delay antibiotic treatment. Our experience of using this test has been very positive. It鈥檚 straight-forward, non-invasive and will have a huge impact on our patients鈥� lives.鈥�

Professor Newman, Theme Co-Lead Lead for Rare Conditions, National Institute for Health and Care Research, Swag直播 Biomedical Research Centre, continued: 鈥淚 am absolutely thrilled with the success of the study and that this test is now being used in routine clinical practice. This test will make a real difference, helping to ensure babies are not going to lose their hearing for a preventable reason.鈥�

It is expected the test could save the NHS 拢5 million every year by reducing the need for other interventions, such as cochlear implants.

Professor Dame Sue Hill, Chief Scientific Officer for England and Senior Responsible Officer for Genomics in the NHS said: 鈥淭his ground-breaking bedside test for detecting whether an antibiotic could cause deafness in babies in intensive care is another example of how the NHS is harnessing the power of genomic medicine to transform patient care. This award is a tribute to the hard work of Professor Bill Newman and his team in Swag直播.鈥�

Dr Gino Miele, R&D Director, genedrive plc, said: 鈥淭he collaboration of our company with the research and clinical team at MFT is a shining example of the NHS working with a commercial company to deliver real improvements in patient outcomes in a cost-effective way.鈥�

Caption: Rachel James, Senior Research Coordinator; Nicola Booth, Research Nurse Manager, Newborn Intensive Care Unit and Dr Ajit Mahaveer, Consultant Neonatologist at Saint Mary鈥檚 Hospital, part of MFT receiving the award on behalf of the PALOH team. (Photo credit: New Statesman Positive Impact Awards)

An international group of leading scientists publish for updating existing standards for determining the disease-causing potential of genomic variants, harnessing insights from Genomics England rare disease participants

The work was led by scientists at Genomics England, Swag直播 and The University of Oxford, coordinating an expert team of scientists and clinicians from academic and healthcare institutions across the UK, US and Australia. The proposed expanded guidelines will enable clinicians and researchers to take better advantage of the full range of variation in whole-genome sequence (WGS) data. They are presented in a paper, 'Recommendations for clinical interpretation of variants found in non-coding regions of the genome,' appearing today in the online edition of the open-access journal .

The recommendations address a major challenge in the diagnosis and understanding of rare disease: to date, most genetic testing has been focused on coding sequence variants 鈥� that is, those variants that disrupt regions of genes that directly encode proteins. The standards and guidelines developed over the past decade for interpreting the results of these tests 鈥� including single-gene assays and gene panels, as well as whole-exome sequencing, which encompasses all of the coding regions of the genome 鈥� have similarly focused on these types of variants.

Yet while these standards have provided a solid, evidence-driven framework for delivering consistent and reliable diagnoses using such tests, coding regions account for at most 2% of the genome. With the advent of affordable WGS and its growing use in clinical practice, ever larger numbers of potentially disease-causing variants of many different types are being detected, but without similarly systematic criteria for the community to assess their impact on disease. The result has been the proliferation of 'variants of uncertain significance鈥� (VUS), some of which have the same downstream clinical impact as pathogenic coding variants but work through different mechanisms and so are more difficult to assess.

In proposing updates to these guidelines for the WGS era, the authors focus explicitly on recommending adaptations and expansions that sit alongside the existing guidance, and using the same strategy of consultation and consensus-building that was used to create them. Taking advantage of Genomics England's leading expertise in clinical WGS, and data from the  participants, the recommendations were drafted by a panel of nine clinical and research scientists from major genomics laboratories in the UK. These include four of the NHS Genomic Laboratory Hubs serving the Genomic Medicine Service (GMS) and the Wellcome Centre for Human Genetics at the University of Oxford. The draft recommendations were tested by an additional group of clinical scientists using 30 test variants; refined by a group of variant interpretation experts from the UK, the  in Cambridge, Massachusetts, and the  and  in Australia, among others.

Dr. Jamie Ellingford , Lead genomic data scientist for rare disease at Genomics England, Research Fellow at Swag直播, and co-lead of the study said: "We are very pleased to be able to present these recommendations to the global clinical and scientific community. We hope that their adoption will serve as a useful starting point for standardising and refining the characterisation of ever more VUS. In doing so we believe that we will be able to target a subset of VUS, and provide guidelines for how to create appropriate functional evidence to interrogate pathogenicity for these variants and deliver more diagnoses for patients in the UK and around the world.

Dr Nicky Whiffin, group leader and Sir Henry Dale, fellow at the University of Oxford and co-lead of the study said: Our aim is to catalyse getting more valuable genetic diagnoses to patients. As we have access to more and more whole genome sequencing data it is becoming increasingly clear that variants in regions of the genome that do not directly encode protein play an important role in rare disease. These recommendations enable us to fully interpret these variants and harness them in the clinic, improving diagnosis and personalised treatment.

A world-first scientific , published today in the New England Journal of Medicine, has shown that whole genome sequencing (WGS) can uncover new diagnoses for people across the broadest range of rare diseases investigated to date and could deliver enormous benefits across the NHS.

The pilot study of rare undiagnosed diseases involved analysing the genes of 4,660 people from 2,183 families - all of whom were early participants in the 100,000 Genomes Project.

Scientists from Swag直播 and Swag直播 University NHS Foundation Trust (MFT), were part of the pilot study team led by Genomics England and Queen Mary University of London. It was carried out in partnership with the National Institute for Health Research (NIHR) BioResource.

Around 14% of the families (302), were recruited from Swag直播.

The ground-breaking Project, led by Genomics England and NHS England, was established in 2013 to sequence 100,000 whole genomes from NHS patients and their families.

The pilot study, led by Genomics England and Queen Mary University of London and undertaken in partnership with the National Institute for Health Research (NIHR) BioResource, found that using WGS led to a new diagnosis for 25% of the participants. Of these new diagnoses, 14% were found in regions of the genome that would be missed by other conventional methods, including other types of non-whole genomic tests.

Many of the participants had gone through years of appointments, without getting any answers. By having their whole genome sequenced diagnoses were uncovered that would not have previously been detectable. The pilot study shows that WGS can effectively secure a diagnosis for patients, save the NHS vital resources and pave the way for other interventions.

Swag直播 was one of the main centres which studied ophthalmic cases, which totalled 321.

The patients taking part donated DNA, derived from a small blood sample. Special machines then sequenced their genomes - the unique sequence of DNA consisting of over three billion letters. It is found in almost every cell in our body.

The first human genome took 13 years to sequence - but now modern technology has shortened that process to about 24 hours, although it does take longer to analyse and make sense of this data.

Some of the important findings are that the integration of these technologies can improve patient healthcare and outcomes. In one example, a 12-year-old boy from Swag直播 received a diagnosis through similar technology in 2015. The youngster, who was blind from birth, was found to have a specific mutation linked to kidney disease and was referred to doctors before the disease had progressed. This resulted in timely treatment for his kidney disease, including dialysis and transplant before the disease progressed to more serious outcomes.

Participants who received a diagnosis through the pilot include:

• a 10-year-old girl whose previous seven-year search for a diagnosis had multiple intensive care admissions over 307 hospital visits at a cost of £356,571. Genomic diagnosis enabled her to receive a curative bone marrow transplant (at a cost of £70,000). In addition, predictive testing of her siblings showed no further family members were at risk.
• a man in his 60s who had endured years of treatment for a serious kidney disease, including two kidney transplants. Already knowing his daughter had inherited the same condition, a genomic diagnosis made by looking at the whole genome for him and his daughter enabled his 15-year-old granddaughter to be tested. This revealed she had not inherited the disease and could cease regular costly check-ups.
• a baby who became severely ill immediately after birth and sadly died at four months but with no diagnosis and healthcare costs of £80,000. Analysis of his whole genome uncovered a severe metabolic disorder due to inability to take vitamin B12 inside cells explaining his illness. This enabled a predictive test to be offered to his younger brother within one week of his birth. The younger child was diagnosed with the same disorder but was able to be treated with weekly vitamin B12 injections to prevent progression of the illness.

For around a quarter of study participants, their diagnosis meant they were able to receive more focused clinical care. This included further family screening, dietary change, provision of vitamins and / or minerals and other therapies.

The study is the first to analyse the diagnostic and clinical impact of WGS for a broad range of rare diseases within a national healthcare system. The findings support its widespread adoption in health systems worldwide.

The high performance of WGS for specific conditions observed in the pilot study - including intellectual disability, vision and hearing disorders of 40-55% diagnostic yield - has underpinned the case for the inclusion of WGS to diagnose specific rare diseases as part of the new NHS National Genomic Test Directory.

The pilot study was also conducted in partnership with the National Institute for Health Research (NIHR) and Illumina who undertook the sequencing, and it was funded by the NIHR, the Wellcome Trust, the Medical Research Council, Cancer Research UK, the Department of Health and Social Care, and NHS England.

Dr Jamie Ellingford from Swag直播 said: “This groundbreaking pilot powerfully illustrates the potential that whole genome sequencing has in diagnosing disease which would otherwise be undetectable. It’s tremendously exciting- and gratifying that the UK leads the world in this area.

“At Swag直播 we’re proud of our reputation as a world leader in genomics; it is the latest of many collaborations with Genomics England which advances how we understand the genome and how we can translate these technologies into excellent patient care."

Professor Sir Mark Caulfield (lead author) from Queen Mary University of London, and former Chief Scientist at Genomics England, said: “We hope this major advance will enable rare disease patients worldwide to start receiving diagnostic whole genome sequencing where appropriate. Our findings show that deployment of this comprehensive and efficient genomic test at the first signs of symptoms, can improve diagnostic rates. This study has paved the way for clinical implementation of whole genome sequencing as part of the NHS Genomic Medicine Service.”

Professor Damian Smedley (lead author) from Queen Mary University of London, said: “This is the first time that whole genome sequencing has been directly embedded into rare disease diagnostics in a healthcare system like the NHS and applied at scale across the full breadth of rare disease. A large proportion of the diagnoses we discovered were found outside the coding region and would not have been detected by existing approaches. This study makes the case for healthcare systems worldwide to adopt whole genome sequencing as the genetic test of choice for rare disease patients.”

Dr Richard Scott, Chief Medical Officer at Genomics England, said: “Historically, diagnosis of rare diseases has often been reliant on clinicians doing multiple different targeted tests - an approach that can delay diagnosis and access to more tailored care. Improved knowledge of genomics and the whole genome sequencing and data infrastructure that the government and NHS have invested in now offers us the ability to radically transform the process. This paper provides evidence of that transformation and where it has most impact. We’re proud at Genomics England to be working in partnership with the NHS to bring the benefits of whole genome sequencing to patients.”

Chris Wigley, CEO of Genomics England, said: “Our mission at Genomics England is to bring the benefits of genomic healthcare to everyone - this pilot study highlights the potential it has to transform healthcare. It gives medical professionals the ability to transform the way patient care is delivered - in particular allowing them to make more accurate diagnoses and offer more personalised treatments.”

Professor Dame Sue Hill, Chief Scientific Officer for England and SRO for NHS Genomics, said: “Understanding the role a person's genome plays in disease holds the key to finding treatments for not only the conditions we know about but also for those we are yet to discover.

“This pilot study highlights the importance of whole genome sequencing within a healthcare system. It can fundamentally change how we think about disease, lead to faster, more comprehensive and accurate diagnoses, provide the missing pieces for families who have a loved one living with a rare disease and pave the way for more tailored and effective treatments for patients.”

Dr Louise Wood CBE, Director of Science, Research and Evidence at the Department of Health and Social Care and Deputy CEO of the NIHR, said: “This study underpinned the UK’s 100,000 genomes project which went on to provide the evidence base for integration of whole genome sequencing into routine clinical care in the NHS. Rare diseases patients and their carers tell us one of their top priorities is getting a diagnosis. This research showed significant progress can be made in addressing this ask and, in about a quarter of cases, in enabling clinical action to be taken on the basis of the diagnosis.”

The GOSH Charity and Sparks National Call is part of an ambition to help unlock breakthroughs in child medicine by supporting researchers’ investigations into the causes of rare diseases in children, and conditions that start in childhood. The funding will also help supercharge their efforts to discover new and better ways to diagnose, treat, and ultimately cure these life-changing and life-limiting conditions.

Researchers based at six institutions across the country will benefit from the cash boost, including Swag直播, University of Warwick, and University College London Great Ormond Street Institute of Child Health, University of Southampton, University of Oxford, and University of Cambridge.T

The successful projects to be chosen for funding include:

• Developing more effective and kinder treatment for Diamond-Blackfan Anaemia, a rare blood disorder that affects the bone marrow’s ability to produce red blood cells, and can cause problems with a child’s growth, immune system, and heart
• Identifying a new treatment to address the underlying mechanisms which cause Dravet Syndrome, a life-limiting form of epilepsy
• Uncovering the underlying mechanisms in acrodysostosis and developing a technique for testing new potential therapies
• Helping to better understand the pain experienced by children with childhood cancer, which could help manage their pain and enhance their quality of life

GOSH Charity and Sparks invited researchers from across the UK to apply for funding as part of its National Call. Of the £2.5 million pledged to support research into some of the most difficult and hard to treat childhood diseases, Sparks contributed £900,000.

£112,500 has been made available by two condition-specific partner charities (Acrodysostosis Support & Research, and Dravet Syndrome UK) to help co-fund research into these diseases.

 Louise Parkes, Chief Executive at GOSH Charity, said: “The impact of research has never been more visible than over the past year, following the development of the COVID-19 vaccine. It shows that essential funding into research can have a life-changing effect on so many people. We’re thrilled that this year’s GOSH Charity and Sparks National Call is investing over £2.5 million into paediatric research projects, with huge thanks to our partner charities, without whom we wouldn’t be able to deliver the National Call. These projects have the potential to deliver kinder and more effective treatments for some of the rarest and most complex conditions and, more importantly, offer children and their families hope for a better future.”

Dr Siddarth Banka from Swag直播 who has received funding said: “I am delighted to have received funding from GOSH Charity which will enable us to further our research to help children with chromatin disorders like Kabuki syndrome and Kleefstra syndrome. It’s fantastic to know that the charity is making such a large amount available for child health researchers across the UK to bid for each year.”

The National Call reflects GOSH Charity’s commitment to paediatric research funding. To find out more about what research GOSH Charity funds, and how Great Ormond Street Hospital has been behind some of the biggest breakthroughs in child medicine, visit .

To find out more about the National Call, and to apply for next year’s funding please visit

A team led by scientists from Swag直播 has discovered how our genome controls the development of many of the organs critical to human life.

The study, published in Nature Communications, casts crucial light on the little understood stretches of DNA that sit between genes.

The work will help scientists and clinicians explain why some babies and children are born with conditions like ‘hole in the heart’.

The research was funded by the Wellcome Trust and Medical Research Council in the UK and involved collaborators in Cambridge and Seville in Spain.

While our 30,000 or so genes hold the code to create every protein in every one of our cells, amazingly this accounts for only about 2% of the DNA, all of which is made up of chemical units called bases. Historically, we used to dismiss the rest of the DNA as ‘junk’.

Since then scientists have realise this vast genetic landscape of so-called non-coding DNA—98% of our genome—actually holds the secrets for controlling how each gene is turned on or off in perfect order.

And that explains how one genome can create each of our different tissues. The problem was, until now, scientists knew little about how this happened at the key stage when human organs are first put together.

Increasingly, where patients are born with conditions affecting their heart, kidneys, brain and limbs but haven’t got an obvious fault in one of their genes, they are having their whole genome read quickly and efficiently by ‘Next Generation Sequencing’ (NGS).

However, scouring the 3 billion of so bases for the single problem is massively challenging—like searching for the proverbial needle in a haystack.

Adapting the same NGS technology, the team has been able to home in on only those parts of the non-coding genome that were functional and discovered it to be about 3% of the total.

By narrowing down the critical areas so significantly and accurately, the work will hopefully help doctors in how they make new diagnoses for patients.

The work also helps us to understand the fundamentals of organogenesis, the key phase during weeks five to eight of pregnancy when the body’s tissues are first assembled from rudimentary progenitor cells.

At this point, ensuring only the right genes are switched on in each different location is vital. We now know the precise patterns of this genetic regulation for each of the organs.

The researchers double-checked their findings in developing zebrafish and laboratory stem cells to show the critical non-coding segments of human DNA could light up green fluorescent protein appropriately, even in fish.

Professor Neil Hanley from Swag直播 and a doctor at Swag直播 University NHS Foundation Trust led the project.

He said: “Fingers crossed this new atlas on the deepest secrets of our genome will help scientists and doctors pinpoint previously unsolved genetic changes, helping to explain to patients and parents where things might have gone wrong.

“And in time, we hope it will begin the process for working out how we might be able to avoid this happening in the future.”

He added: “What was striking was not just how particular sets of critical genes were turned on at the right time in the right place but how critical it was for the wrong genes to be shut off.

“In effect, you could tell as much about the heart by understanding why it wasn’t a kidney or a lung

”We hope this new level of understanding will really help stem cell researchers benchmark the authenticity of the cells they are growing in the laboratory.”

The paper ‘Dynamic changes in the epigenomic landscape regulate human organogenesis’ is available

A team of students from have won an award for genetically modifying bacteria to produce kinder hair-dyes.

The eight students, with academic guidance from the , the , and the , genetically engineered E. coli bacteria to secrete proteins which could colour, repair, straighten, and fragrance hair.

For their work, they were awarded a gold medal in the (iGEM) competition. The focus of iGEM is to provide a synthetic biology-based solution to a real-world problem.

The project aimed to explore an alternative to current hair-dyes which use often harmful chemicals, leading to allergic reactions in users, as well as environmental damage if not disposed of properly. They can also cause bleaching and brittle hair, and have been tentatively suggested as a potential carcinogen.

“The initial idea,” said Elisa Barrow Molina, a third year biotechnology student, “came from an article we saw about how hair dyes could cause alarming reactions in some users.”

The students genetically modified a strain of E. coli which naturally adheres to hair to secrete a dye, replacing the use of potential pollutant and carcinogens.

After this initial idea, they also realised they could modify the bacteria to secrete other products, such as proteins to repair hair, and compounds to fragrance it. Through experiments, the students showed that their engineered bacteria were resilient when exposed to stresses such as chlorine or shampoo.

They encountered several challenges during the process, though the biggest one “depends on who you ask!”, as the division of labour meant they were all meeting and overcoming different headaches during their work.

Camilo Albornoz Carranza, a third year neuroscientist, says; “The synthetic biology was out of my comfort zone, but winning a gold medal vindicates all the work we put in.”

On this note, the students are all in agreement. “This shows we did something worthwhile,” they say, considering it justification for the three months of lab work they put in over the summer. The award from iGEM “closes the chapter”, says Elisa.

“That’s the thing about iGEM,” adds Sophie Guillemot, a third year chemist, “it’s about bringing ideas to the table and leaving them for the next team to develop further.”

While they are not currently planning to commercialise the bacteria, the students also carefully considered potential safety concerns should their product ever make it to market. To address these, the students designed and computationally modelled two genetic ‘kill-switches’, which would prevent the engineered bacteria either surviving away from hair, or developing pathogenicity.

“In ten or twenty years,” notes second year molecular biologist Thomas Harrison, “I think genetically modified bacteria will be part of our lives on a very intimate, primary level.”

The project was initially financed by the University, but the students also sought out sponsors and private donors. They also consulted with the public and hair care experts, which resulted in the introduction of a straightening protein to their final design, as well as the exploration of a large range of colours.

Going forward, the team plan to focus on their individual degrees. For some of them, the iGEM project has helped them to decide where they would like to work in the future. Mujtaba Ansari, a third year biotechnology student, says; “By participating, I’ve discovered that I really like research and lab work, and it’s definitely something I’d like to do in the future.”

Prof Eriko Takano, supervisor of the iGEM team says “We are now looking for enthusiastic students to join the next year’s team. This is a great opportunity, not just for biology students but for students from all faculties who want to explore the revolutionary impact of new technologies and push their skills to new limits”.

Hereditary spastic paraplegias (HSP) are a group of genetic disorders that cause weakness and stiffness in the leg muscles. Generally symptoms gradually get worse over time, and severely affected patients are wheelchair dependent.

Changes in several genes are known to cause HSP. However, the underlying cause in a substantial number of patients remains unknown. Currently, there is no cure for HSP.

Via human genetic studies and international collaboration, teams in Swag直播 and Amsterdam worked together to identify a new cause of HSP. They found that this disease is caused by mutations in a gene called PCYT2, which caused the gene to be less active.

The researchers studied the effects of the condition using zebrafish and cell samples from patients with the disease.

They found that zebrafish with normal or reduced PCYT2 activity had significantly better survival rates than those with absent PCYT2 activity, leading Dr Siddharth Banka – Clinical Senior Lecturer at Swag直播 and Consultant Clinical Geneticist at – and his colleagues to conclude that complete loss of PCYT2 activity is likely to be, ’incompatible with life in vertebrates’.

The gene encodes an enzyme which produces a lipid (a fatty molecule) that is used to build cell membranes in every cell of the body. The lipid produced by the enzyme is particularly abundant in brain cell membranes.

A team in Amsterdam was also able to identify abnormal biochemical signatures in the cells and blood of the patients who donated samples. It is hoped that these signatures could be used as markers to help diagnose patients with the condition.

Dr Banka runs a Clinical Genetics clinics at , which is part of MFT. His research group uses a combination of genomics, clinical and functional studies to identify the cause of disease in patient with unsolved genetic conditions.

Dr Banka said: “Saint Mary’s Hospital is one of the leading NHS and internationally recognised large-scale providers of genomic services. Being able to combine my clinical role at the hospital, with my academic research at Swag直播, has been crucial to this outcome.

“This link between academia and the NHS means we can translate research from the bench to the bedside, for the benefit of our patients.

“The identification of more patients in future will help in better understanding of the effects of HSP.”

It is thought that studying this crucial gene will help in understanding other types of HSP and other neurodegenerative diseases.

The paper was published in the neurological journal .

A team at Swag直播 have developed a novel stem cell gene therapy approach to treat children with a devastating genetic disease. The approach is currently being developed for clinical trial in patients with the disease.

Hunter disease affects the bones, joints, hearts and lungs of affected children and in about two thirds of cases also affects the brain, leading to severe mental disabilities. It is a genetic disease inherited by affected boys, caused by the missing IDS gene.

Although there is an existing enzyme replacement therapy available currently on the NHS, it costs more than £150,000 per year per patient and doesn’t penetrate to the brain.

’s team at Swag直播 developed a stem cell gene therapy approach that works by replacing the missing gene in the bone marrow of affected children. To make this more effective, they also added a tag to the IDS enzyme to allow it to pass into the brain.

The team demonstrated complete correction of both the bone, joint and brain disease in mice, recently published in the journal .

Prof Bigger said “We expected the stem cell gene therapy approach to deliver IDS enzyme to the brain, as we have shown previously for another disease: Sanfilippo types A and B, but we were really surprised to discover how much better the tag made the therapy in the brain.

“It turns out that the tag didn’t only improve enzyme uptake across the blood brain barrier, but also improved uptake of the enzyme into cells and it appeared to be more stable in the bloodstream – all improvements on current technology.”

The team are part of the recently awarded InnovateUK Swag直播 Advanced Therapy Centre Hub (iMATCH), and aim to develop this therapy within this framework to take it to clinical trial.

A video describing the effects of the disease and potential of gene therapy can be seen  in Living Beyond Hope: A Short Documentary by Joshua Davies.

He added: “We are extremely grateful to our charity funders without whom this work would not have been possible, including the Isaac Foundation, the National MPS Society and the Newlife Foundation.

Ther image isn used on the cover of the journal .

An international team of scientists and doctors has identified a family of five new genetic diseases which are likely to affect more than 1 in 5000 children.

The discovery of the diseases, which cause combinations of developmental delay, and problems with growth, heart, kidney and other organs, has important implication on diagnosis and treatment.

The study, led by from Swag直播 and the Saint Mary's Hospital, is published in the reputed American Journal of Human Genetics.

The diseases are the result of abnormalities in genes dedicated to regulating the processes that control DNA modifications and gene expression – known as master regulators.

A hundred patients mostly in the UK -have already been identified with the diseases – coined by the team as histone lysine methylation disorders.

Though there are no epidemiological studies, the team believe at least 1 in every 5,000 children are affected.

Dr Victor Faundes, a PhD student in Dr Banka’s lab studied genetic variants in a group of master regulators called 'histone lysine methylases and demethylases or KMTs and KDMs.

He compared the genetic variants in KMTs and KDMs in children with developmental problems and the general population.

He said: “I found that some specific types of genetic changes that interfere with function of some KMTs and KDMs were commoner in children who had problems with development of their brains or other organs.

“These results tell us that KMT and KDM mutations explain the diagnosis in a disproportionately large number of children with developmental disorders.

“This is an important discovery because we already know that some drugs can control the activity of KMTs and KDMs and thus could be potential treatments for these conditions.”

Dr Banka said: “This is very exciting because in addition to giving an idea of the scale of the problem, this has also enabled us to identify five new genetic disorders.

“Our findings have helped in providing diagnoses in children in whom the underlying cause for their medical condition was previously a mystery”.

He added: “We are now planning more detailed studies to understand the biological link between the mutations and the clinical problems.

“And we are also trying to identify more patients with these disorders that will help in revealing the full clinical spectrum of these conditions.”

Doctors and scientists are unable to deal with individual enquires from the public. However, patients should in the first instance contact their GP who may refer them on to a local geneticist.

Journalists who wish to see a copy of the journal article should contact the American journal of human genetics directly on jcaputo@cell.com or press@cell.com The paper is available

Figure : Histones are proteins that are in contact with DNA, and they help to fold or unfold the DNA in order to regulate gene expression. The fold/unfold state depends on chemical modifications of histone tails such as methylation or demethylation. These modifications are carried out by KMT and KDM.

An international collaboration led by scientists and doctors from the UK, Netherlands and United States has identified a new genetic disease that affects the size of our brains and causes severe developmental problems. 

While working on another project, Dr Siddharth Banka who is based at Swag直播 and the , Saint Mary's Hospital, noticed three children with large or small brains, developmental delay and mutations in a gene called RAC1. 

At that point, it was difficult to be sure if it was a true finding, because RAC1 has never before been linked to human disease. And mutations in no other single gene have previously shown this extent of variability in brain-size. 

As part of a parallel project, Professor Han Brunner and Dr Margot Reijnders of the Radboud University in Nijmegen had gathered together four more children with mutations in the same gene and altered brain-sizes. Some of the affected children were also found to have epilepsy and heart defects.

Dr Tom Millard also from Swag直播 then used mouse cells to show that mutations in RAC1 affect the shape of the cells. When Dr Maria Kousi and Professor Nicholas Katsanis of Duke University, North Carolina found a similar effect of RAC1 mutations in brain-size of zebrafish, the team had no doubt they had discovered something new. 

The study is published in the American Journal of Human Genetics. 

“Evolution has tinkered with thousands of genes over millions of years, to shape the human brain, an organ that is remarkably consistent in its appearance and size across billions of people,” said Dr Banka. 

He added: “However, occasionally a tiny little alteration in just one of these thousands of genes can have devastating effects, reflecting the fine balance of this complex genetic orchestra.”

Dr Reijnders said: “Remarkably, evolution has hardly meddled with RAC1. In fact, the RAC1 of the humble roundworm is not very different from the RAC1 present in your and my cells. 

“This astonishing conservation across eons indicates the fundamental role of RAC1 in life. Hence, in some ways it is not surprising that a small alteration in this gene is difficult for us to tolerate.” 

Professor Han Brunner added: “These findings open new doors to our understanding of the development of the brain. 

“We suspect RAC1 plays an important role in other genetic diseases as well”. 

Dr Banka added: “We are sure that this discovery will lead to identification of more patients with RAC1 mutations, who have not yet been diagnosed. 

“The next step for the scientists will be to use this knowledge to work out possible treatments for this disease and related conditions.” 

Part of the study was based on the genetic data from the Wellcome Trust Sanger Institute in Cambridge.

The doctors and scientists who took part in this study are unable to deal with individual clinical enquires from the public. However, patients and families should in the first instance contact their GP who may refer them on to a local geneticist.

A study into a new treatment for Sanfilippo disease, a rare and fatal condition which causes progressive dementia in children, is progressing well with results set to be published later this year.

Also known as Mucopolysaccharidosis (MPS) III, there is currently no effective treatment for the condition which affects around 150 children in the UK.

Sanfilippo disease is diagnosed in childhood, with sufferers experiencing deafness, hyperactivity and behavioural problems, progressive developmental delay, and seizures during the later stages of the condition. It is usually fatal in late childhood or early adulthood.

The study aimed to establish whether high doses of the treatment Genistein Aglycone was effective. Patients with Sanfilippo disease have too much of the substance heparan sulphate in their cells, particularly cells in the brain, because they lack the enzyme that usually breaks the heparan sulphate down. It is thought that Genistein Aglycone works by blocking the production of heparan sulphate and associated damage to the cells.

Genistein is a naturally occurring chemical found in soya beans. In the study the researchers used a synthetic version, Genistein Aglycone, to maximise absorption through the gut.

Previous research has shown that low doses of Genistein reduce the heparan sulphate in the blood and urine, but are not sufficient to be effective in the brain. However, research at Swag直播 using higher doses of Genistein Alygone in the mouse model of Sanfilippo disease has shown that this is effective in reducing neurodegeneration.

All 22 patients were recruited within the allocated time frame. Monitoring of the final participant to join the trial will be complete in July, after which the results will be published.

The study was funded by charity The Society for Mucopolysaccharide Diseases (The MPS Society) and the GEM Appeal. It was conducted by Swag直播 and the  at The Royal Swag直播 Children’s Hospital.

Patients received either Genistein Aglycone or placebo (an inactive substance that looks like the treatment) with food, over a period of 12 months. After that, all children received Genistein Aglycone for a further 12 months. Participants attended regular clinic visits to have levels of heparin sulphate in the spinal fluid measured, alongside other assessments.

Dr Simon Jones, Consultant in Paediatric Inherited Metabolic Disease at , Swag直播 and Honorary Senior Lecturer at Swag直播, who is leading the study explains: “This was the first study to test the effectiveness of higher doses of Genistein, to assess whether it has an effect on the brain of patients with Sanfilippo disease. Now that we are nearing completion of the trial, we will soon be in a position to publish those findings.

“We know how distressing this condition can be for children and their families. During the later stages of the disease, patients experience seizures, become wheelchair bound and can have trouble swallowing. Conducting research into rare conditions like Sanfilippo disease is important to help us provide patients with the best possible care.”

, Chief Scientific Investigator for the study from said: “We would like to thank all of the families who have supported this study whether that has been by raising the vital funds to deliver the study or by deciding to take part in the study. We eagerly anticipate the results of the trial and hope that this may ultimately result in a potential treatment for Sanfilippo disease.”

The delivery of the study was supported by the .

University of Swag直播 biologists have discovered that breast tissues have 24-hour body clocks, and that several hundred genes are regulated in a daily cycle.

The discovery by and , may offer the first evidence of a link between breast biology - including breast cancer risks - and the body clock.

They found that ageing of breast tissue has a central role in controlling these clocks.

Breast tissues get stiffer as they get older which, the authors find, causes the clocks to get weaker.

Higher mammographic density - or breast tissue stiffness - is a known risk factor for breast cancer, but the way that stiffness contributes to cancer is not known.

Funded by and , the Swag直播 biologists have now discovered that the amplitude (strength) of clocks within breast cells is dependent on the biological stiffness of the tissue.

They also found that body clocks are needed for the production breast stem cells.

The weakening of clocks in ageing may therefore reduce normal stem cells, and it may help cause the tissue to become cancerous.

The study is published in Nature Communications today.

Dr Meng said: “We have discovered that tissue stiffness contributes to the age-dependent dysregulation of both clocks and stem cell function in the breast tissue.

“We identified some of the clock target genes within breast tissue, which are known to be involved with tumour formation.

“There is now a widening interest in the importance of stem cells for the formation of breast cancers – so our findings in relation to that are of much interest”.

Professor Streuli said: “A lot of epidemiological work links both breast tissue density and body clock disruption to the risk of getting breast cancer.

“And now for the first time we've identified a biological link.”

All tissues have 24-hour clocks, causing the amounts or activities of proteins in their cells to go up and down every day.

We know the clocks are important for normal breast function, because genetically deleting one of the clock genes contributes to nursing defects.

They also found that stiffening of breast tissue with age causes their inbuilt clocks to get weaker. And the study shows how this works at the molecular level.

The paper, is published in Nature Communications. doi:10.1038/ncomms14287

Cancer

 is one of Swag直播’s - examples of pioneering discoveries, interdisciplinary collaboration and cross-sector partnerships that are tackling some of the biggest questions facing the planet. #ResearchBeacons

A young Mum has been able to graduate from Swag直播 with a PhD, thanks to the support and encouragement the University offers to female early career researchers.

Dr Heather Robinson, 30, was working for a pharmaceutical company when she received a fully-funded place on the Evolutionary Genetics masters course at Swag直播. After finishing this and taking a year off, she returned to Swag直播 to work on ancient DNA and microbial ecology.

When she fell pregnant with her second child at the end of her first year, her supervisors enabled her to take 10 months of leave, and when she returned they gave her complete flexibility in her working hours and around-the-clock access to labs and workspace. This enabled her to finish her PhD in 4 and a half years, as opposed to the 6 or 7 it would have taken if she had worked part-time.

Her research involved finding magical and medicinal substances inside ancient African ritual figurines, and identifying the contents of Roman Amphoras at The Swag直播 Museum. Her choice to pursue her PhD at Swag直播 was heavily influenced by the fact that it is one of few British universities to have custom-built Ancient DNA laboratories.

She is now working as a Health Data Analyst in the University’s Faculty of Biology, Medicine and Health, where she looks at regional child height and weight measurements and BMI trajectories, and uses data to predict medical conditions. She hopes to stay at Swag直播, both to research and to teach.

“The University has a strong female representation in life science roles, which makes long-term STEM careers seem more feasible to early career researchers. I am proud to be an alumnus.

“It is important to me that my children see me working, even when this has been difficult - it has already changed my son’s view of women’s roles in society, and I am sure it will influence my daughter. They are both very excited that their Mummy is a Doctor!”

Two gene mutations that trigger a retinal disease that causes blindness in one in 5,000 males have been mapped, leading to the potential for new therapeutic treatments.

Researchers from Swag直播 undertook a structural analysis of X-linked Retinoschisis (XLRS), a genetic disease leading to a type of macular degeneration in which the inner layers of the retina split causing severe loss of vision and gradual blindness. Currently, there is no effective treatment for XLRS, with research focused on understanding how the disease occurs in the retina.

XLRS is caused by mutations in the retinal protein retinoschisin. The protein plays a crucial role in the cellular organisation of the retina, assembling itself to form paired octameric (consisting of eight retinoschisin) rings. The rings each resemble an 8-bladed propeller. This new structural insight yielded important clues into how retinoschisin performs its crucial role in the retina and spurred efforts to investigate what happens to this structure when it is mutated in XLRS.

Using a cryo-electron microscope, the team examined the paired rings as well as the effects on the rings of two XLRS-causing mutations. The effects of these mutations, despite being reported to cause the disease, were unknown and may offer explanations on how the normal protein functions in the retina.

, Professor of Biochemistry at Swag直播 and lead author of the research team’s resulting paper, said the cryo-electron microscopy allowed them to identify the location of the mutations on the rings.

“We found that one disease-causing mutation sits in the interface between the octamer rings, causing retinoschisin to be less stable. The other mutation is on the propeller tip which we think is a novel interaction site for other binding proteins in the retina.”

As well as identifying the mutations and precisely mapping their locations, the research team held out the possibility that future work could lead to genetic interventions and treatments, which could limit or prevent the damage caused by XLRS.

“XLRS is a promising candidate for gene therapy, so our findings on these two different classes of mutations will be informative for future therapeutic strategies,” concluded Professor Baldock.

The paper, entitled ‘’, was published in the journal Human Molecular Genetics. doi: 10.1093/hmg/ddw345

A gene dubbed the ‘Teashirt’ by its discoverers has been identified as a link between children with kidney problems and autism, in a new study which has implications for how doctors working on both conditions administer tests to their patients.

The new paper, published in the journal Nature Genetics, was led by the Developmental Biology Institute of Marseille, collaborating with Swag直播, and it describes the effects of mutations of Teashirt in people and mice.

The gene, formally named Tshz3, had already been implicated by the joint research team in 2008 as being essential for development of smooth muscle in the wall of the ureter. Mutant mice were born with ‘blown-up’ kidneys because their ureters failed to actively propel urine down to the bladder.

Professor Adrian Woolf from Swag直播, then working as a children’s consultant in London, discovered that one of his patients born with abnormal kidneys had a deleted Tshz3 gene and also displayed characteristics of autistic spectrum disorder.

The French team also realised that mice with Tshz3 mutation not only had kidney problems but also displayed learning difficulties.

The findings sparked a global search of other kidney clinics, which returned ten more patients with similar symptoms. After genetic testing, it was confirmed that the same gene was missing in all of them – findings which are published in the new paper.

Professor Woolf said: “The mutant mouse kidney looks just like ‘hydronephrosis’, the distended kidney seen in about 1 in 1,000 individuals when they are screened by sonar scans as unborn babies. It now appears that this gene is linked to at least some of these cases and that it also has implications for how our brains work in childhood.”

The research was led by Professor Laurent Fasano in Marseille who discovered the teashirt gene in fruit flies in 1991. He said: “The sooner the better; early detection of this new condition will favour early behavioural therapies, which is good for the kids and their family.”

The link between the two diseases has implications for how doctors work with patients who display either kidney or learning problems.

Professor Woolf, who is also a consultant at the Royal Swag直播 Children’s Hospital where he runs a renal genetics clinic, added: “A fairly simple genetic test on patients being treated for either kidney problems or autistic spectrum disorder could identify whether the Teashirt gene is missing and also highlight that the patient may need investigation for the other condition. Time will tell whether TSHZ3 plays a role in many more cases than we’ve currently been able to identify.”

The paper ('Tshz3 deletion causes an autism syndrome and defects in cortical projection neurons' ; DOI 10.1038/ng.3681) will be published in the journal Nature Genetics on 26 September 2016. Research was part-funded by the Medical Research Council.

The cause of a disease that targets blood vessels in the brain – leading to multiple debilitating symptoms and, often, to early death – has been tracked to a single mutated gene, opening up the immediate possibility of improved patient care through genetic testing, and of future treatments.

The research, conducted over 12 years, was led by the teams of Professor Yanick Crow and Dr Ray O’Keefe from Swag直播’s , and included contributions from over 60 academics and scientists from around the world. It was published in the journal Nature Genetics.

This discovery involved the identification of mutations in SNORD118 – a small nucleolar RNA (snoRNA) gene – to cause leukoencephalopathy with calcification and cysts (LCC). LCC is characterised by progressive white matter degeneration in the brain. The disease can present in patients at any stage of life.

Dr Emma Jenkinson, Research Associate at Swag直播’s , was lead laboratory researcher on this project. She said that the 12-year study unlocked greater understanding of the development of genetic disorders caused by mutations in non-coding regions of the genome: “The identification of SNORD118 as the instigator of a progressive and frequently fatal brain disease is a very significant step forward in understanding the role of non-coding RNAs in the development of certain diseases.

“Although LCC is relatively rare, by understanding the mechanism of this disease we may be able to extrapolate similar research into other diseases in the future – with the ultimate long term aim being the discovery of new treatments for patients.”

The team collected biological samples and clinical data from 33 families affected by LCC, and used mapping techniques combined with next generation genome sequencing to identify the mutated gene. That then provided the team with evidence of 36 rare sequence variants, of which several were shown experimentally to cause a dysfunction of the snoRNA.

The paper, entitled ‘Mutations in SNORD118 cause the cerebral microangiopathy leukoencephalopathy with calcifications and cysts’ was published on 29 August in .

A team led by from Swag直播 found that the anti-inflammatory drug completely reversed memory loss and brain inflammation in mice.

Nearly everybody will at some point in their lives take non-steroidal anti-inflammatory drugs; mefenamic acid, a common Non-Steroidal Anti Inflammatory Drug (NSAID), is routinely used for period pain.

The findings are published today in a paper authored by Dr Brough and colleagues, in the respected journal Nature Communications. Dr Brough and supervised PhD student Mike Daniels, and postdoc Dr Jack Rivers-Auty who conducted most of the experiments.

Though this is the first time a drug has been shown to target this inflammatory pathway, highlighting its importance in the disease model, Dr Brough cautions that more research is needed to identify its impact on humans, and the long-term implications of its use.

The research, funded by the Medical Research Council and the Alzheimer’s Society, paves the way for human trials which the team hope to conduct in the future.

Around 500,000 people in the UK have Alzheimer’s disease which gets worse over time, affecting many aspects of their lives, including the ability to remember, think and make decisions.

In the study transgenic mice that develop symptoms of Alzheimer's disease were used. One group of 10 mice was treated with mefenamic acid, and 10 mice were treated in the same way with a placebo.

The mice were treated at a time when they had developed memory problems and the drug was given to them by a mini-pump implanted under the skin for one month.

Memory loss was completely reversed back to the levels seen in mice without the disease.

Dr Brough said: “There is experimental evidence now to strongly suggest that inflammation in the brain makes Alzheimer’s disease worse.

“Our research shows for the first time that mefenamic acid, a simple Non-Steroidal Anti Inflammatory Drug can target an important inflammatory pathway called the NLRP3 inflammasome , which damages brain cells.”

He added: “Until now, no drug has been available to target this pathway, so we are very excited by this result.

“However, much more work needs to be done until we can say with certainty that it will tackle the disease in humans as mouse models don’t always faithfully replicate the human disease.

“Because this drug is already available and the toxicity and pharmacokinetics of the drug is known, the time for it to reach patients should, in theory, be shorter than if we were developing completely new drugs.

“We are now preparing applications to perform early phase II trials to determine a proof-of-concept that the molecules have an effect on neuroinflammation in humans.”

Dr Doug Brown, Director of Research and Development at , said: “Testing drugs already in use for other conditions is a priority for Alzheimer’s Society - it could allow us to shortcut the fifteen years or so needed to develop a new dementia drug from scratch.

“These promising lab results identify a class of existing drugs that have potential to treat Alzheimer’s disease by blocking a particular part of the immune response. However, these drugs are not without side effects and should not be taken for Alzheimer’s disease at this stage – studies in people are needed first.”

, published in the journal . DOI: 10.1038/NCOMMS12504

Please note, this study is experimental and doctors do not prescribe Mefenamic Acid as a treatment for Alzheimer’s Disease. For queries about treatment and care, please contact Alzheimer’s Society on 0330 333 0804. or email enquiries@alzheimers.org.uk

A molecule which, for the last 20 years has been believed to be an indicator of good prognosis in tumours has been shown to have a dark side by new research from The Universities of Swag直播, Athens and collaborators, recently published in Nature Cell Biology.

The molecule p21WAF1/Cip1 (or p21 for short) is often found in association with a so-called ‘master tumour-suppressor’ p53. This has traditionally given doctors an indication that there is a good prognosis for cancer – the presence of p21 indicating that the p53 tumour suppressor will lead to a less aggressive tumour.

However, the new study has presented evidence that turns this assumption on its head. Scientists at Swag直播, part of , alongside international collaborators, especially at the University of Athens, have shown that in tumours where the p53 molecule is deficient, p21 dramatically increases the ability of tumours to grow and spread throughout the body.

, one of the lead authors, along with senior author, Professor Vassilis Gorgoulis, Honorary Professor in Swag直播, and Professor-Director, University of Athens, have said: “Years ago, being exposed to a lot of sunshine was thought to be one of the best ways of being healthy before we realised the harmful effects of too much could have.

“This protein has a similar effect. When the activity of wild type p53 is lost, excess production of p21 is far from a good thing. This protein which was previously thought benign turns out to have a dark side.”

The findings are a result of five years’ of study into p21, originally with a view to developing treatments, which increase its presence and supress tumours. While conducting this investigation the international research team noticed that in p53-deficient tumours increased p21 was actually correlating aggressive behaviour. This led them to suspect a different possibility for how the molecule was working in tumours.

In reality, p21works by deregulating the DNA replication machinery and triggering what's called replication stress. This causes genomic instability, a key hallmark of cancer.

The new findings open up the possibility of treatments being developed which counter p21, an avenue of research which has not been previously explored.

Professors Townsend added: “We now know that p21, when unleashed from p53 control, is a factor in causing the danger signs of cell replication found in aggressive tumours. Although this goes against what we have known to date, it offers the hope of developing new treatments for cancer in the years ahead.”

The paper, ‘,’ (doi:10.1038/ncb3378) was published in the journal Nature Cell Biology.

Research was carried out at Swag直播, the University of Athens with contributing authors also from the UK, Spain, the Czech Republic, Sweden, USA, Denmark and Switzerland.

is one of Swag直播’s research beacons - examples of pioneering discoveries, interdisciplinary collaboration and cross-sector partnerships that are tackling some of the biggest questions facing the planet.

Swag直播 has opened the multi-million pound Stoller Biomarker Discovery Centre (14 June), which will identify the unique markers of diseases such as cancer or arthritis. These markers will be developed to ensure the right treatment for the right patient as early as possible.

The Stoller Biomarker Discovery Centre, which is funded by a philanthropic gift from the Stoller Charitable Trust, and in partnership with , will help to industrialise the process of identifying biomarkers – the molecular clues that indicate the presence of a disease or other condition.

By detecting these on a scale never seen before in Europe, University scientists and clinicians will be able to work with health companies and the NHS to produce a greater number of tests and develop new treatments to accelerate the process of curing many of the most serious illnesses faced today.

Medicines have historically been developed for whole populations, but biomarkers help to stratify patients so they get the right treatment for them – not one size fits all. In cancer work already ongoing in the Centre has identified possible tests to detect ovarian cancer earlier, gaining valuable advantage by being able to treat this disease earlier and therefore more effectively.

is the Director of the new Centre. He said: “The Centre is a major step forward in precision medicine. Essentially this is the future of healthcare – getting the right treatment to the right person at the right time and in the right dose.

“Without the knowledge of biomarkers we won’t be able to identify which people need treatment or who will benefit from certain medicines, so this new centre underpins everything we’re doing in precision medicine in Swag直播 and beyond.”

The Stoller Biomarker Centre is located at , in the midst of biotechnology companies, t and Swag直播.

The new Centre is stocked with a large suite of high-end SCIEX mass spectrometers, including TripleTOF^® 6600 Systems with SWATH Acquisition, QTRAP^® 6500+ Systems, and the SCIEX Lipidyzer Platform, for measuring molecules in proteins (proteomics). Swag直播 has also invested in a number of liquid chromatography and automated sample preparation components for the Centre, from SCIEX and other life science companies.

“SCIEX’s mission of innovating integrated, reliable analytical tools to gain scientific understandings that lead to better health, enables our customers to advance precision medicine with scale and speed like never before,” said Jean-Paul Mangeolle, President of SCIEX.

“And it takes more than providing great instruments to be part of a movement as important as precision medicine; it takes strong collaborations with customers, partnerships with industry leaders and teamwork with our colleagues at other the Danaher Corporation life companies, to establish and deploy the most comprehensive proteomics solutions.”

The Centre was officially opened during a special two day conference (14-15 June), which attracted some of the biggest names in medical research such as Dr Leroy Hood, Dr Leigh Anderson, and Professor Jennifer Van Eyk.

The Centre will build on research carried out at Swag直播 including discovering new markers for the earlier detection of cancers – crucial in starting early treatment to save lives. Work to identify new biomarkers for diseases such as arthritis, cardiovascular, Alzheimer’s and psoriasis will also be enhanced.

The Centre will work in the newly devolved healthcare system in Greater Swag直播, as the city-region and major bodies and companies operating within it work to remove bottlenecks such as making the transition from lab to bedside with new tests and drugs.

President and Vice-Chancellor of Swag直播, said: “Swag直播 has become a major hub for precision medicine and proteomics we are very grateful to the funders who have backed the cutting-edge work that is carried out by our scientists.

“As a result of their generosity, The Stoller Biomarker Discovery Centre will start work on addressing some of the biggest issues in medicine in an environment where these discoveries can move quickly to improve people’s lives.”

Scientists in Swag直播, who have developed a stem cell gene therapy to reverse a fatal childhood illness, have agreed to work with a new therapeutics company to test it in a human trial.

University of Swag直播 and Central Swag直播 University Hospital NHS Foundation Trust () researchers have developed the pioneering approach for Sanfilippo disease (also known as mucopolysaccharidosis type III or MPS III) – a genetic condition for which there is currently no effective treatment.

The most common of the four types of Sanfilippo (type A) affects around 100 children in the UK, or one in 89,000 births, and it is this type that is targeted by the new treatment.

Sanfilippo is caused by a lack of the SGSH enzyme, which helps to break down and recycle long chain sugars. This results in a build-up of sugars in the body and particularly the brain.

Children with Sanfilippo begin showing symptoms of hyperactivity, severe behavioural problems and miss developmental milestones as toddlers. As they get older they show symptoms similar to dementia, and most never achieve a mental age beyond two years. Later they will experience seizures and difficulties in walking and swallowing. It is invariably fatal, with most children dying around the age of 18 years.

Following a licence agreement with , a new UK-based clinical-stage biotechnology company, the gene therapy developed in Swag直播 will be trialled in humans. Swag直播’s technology transfer company, , negotiated the terms of the major deal with Orchard Therapeutics.

, who leads the Stem Cell and Neurotherapies Laboratory at Swag直播 and developed the technique in partnership with the Trust scientists, said: “This license agreement with Orchard will allow us to take the technique we have developed to the next and crucial stage of trials in humans. We are hopeful that this treatment may help to treat the early onset dementia in these patients and saving children’s lives.

“If we can show that it is possible to treat single gene brain diseases, such as Sanfilippo, with stem cell gene therapy, this will pave the way for treating other lysosomal storage and neuro-metabolic disorders.”

The treatment works by genetically correcting the patients’ own stem cells and implanting them into bone marrow to release the missing enzyme in a way that reaches the brain, thereby correcting the condition.

The new study will take place at CMFT, supported by .

“There are currently no effective treatments available to children affected by Sanfilippo disease. We hope that this work will help to halt the progression of this devastating condition,” added Dr Simon Jones, Consultant in Paediatric Inherited Metabolic Disease at Saint Mary’s Hospital and the Swag直播 Centre for Genomic Medicine.

Professor Robert Wynn, Consultant Paediatric Haematologist at Royal Swag直播 Children’s Hospital and chief investigator for the clinical study explained: “This new clinical study aims to explore whether we can use stem cell gene therapy to produce blood cells that express corrected versions of the missing enzyme.

"We know that in conditions similar to Sanfilippo blood cells from a bone marrow donor can deliver such enzymes effectively. This new gene therapy builds on the decades of experience of CMFT physicians in bone marrow transplantation of children with these other metabolic diseases.”

Earlier attempts to cure the illness with a bone marrow transplant were unsuccessful as not enough enzyme was produced to have an effect, but the Swag直播 team has developed a way of overproducing the SGSH enzyme specifically in bone marrow white blood cells.

This was achieved by developing a lentiviral vector – a tool commonly used by molecular biologists to deliver genetic material into cells – specifically for use in humans, which will be tested in the trial. The lentiviral vector delivers the SGSH gene to bone marrow cells, which, when implanted into the body are able to traffic to both the bone marrow and the brain and deliver SGSH enzyme throughout the body, thus correcting the disease.

Recently a related illness metachromatic leukodystrophy has been treated by Italian scientists using a similar approach, with extremely promising results in patients.

The Swag直播 team used a similar lentiviral vector to the Italian team, but improved the design to make it more specific to the white blood cells that traffic into and engraft in the brain after a bone marrow transplant (monocytes/microglia). This improves brain targeting and effectiveness.

Professor Bobby Gaspar, Chief Scientific Officer of Orchard Therapeutics said:

“Stem cell gene therapy has shown promising effects in several different diseases and we are hopeful that this technology will change the lives of children with Sanfilippo type A and other monogenic bone marrow disorders in the near future.”

Life Sciences Minister, George Freeman MP, said: “This pioneering trial, led by UK researchers in partnership with a UK company, underlines exactly why we invest £1 billion each year through the National Institute for Health Research.

“This new gene therapy has the potential to change the lives of children with this dreadful condition, and will undoubtedly help to cement the UK’s position as a world-leader in medical research.”

Vast amounts of data generated by screening patients for diseases like cancer and arthritis at Swag直播 will now be used to improve treatment and drug safety in partnership with the University of Dundee.

The two universities have joined forces to transform medical treatment through protein analysis technology which identifies biomarkers of disease. This allows doctors to target treatments specific to the patient’s condition, and deliver the right treatment at the right time in the right dose.

This ‘precision medicine’ approach improves safety and effectiveness as patients are treated on an individual basis.

The new partnership will use data from work on and inflammatory disease biomarkers led by which is pioneering the application of ‘proteomics’, the large-scale analysis of proteins using state-of-the-art mass spectrometry instruments.

This enables the screening of patients for new protein diagnostic and disease markers and the segmentation of patient groups which can benefit from specific therapies and drug treatments.

This approach can also help reduce the risk of patients receiving treatments that cause harmful side-effects. In one example of the potential of this work, Professor Whetton and colleagues recently discovered a new biomarker for risk of ovarian cancer.

Professor Whetton said: “We are industrialising the approach to finding new biomarkers of diagnosis, prognosis and responses to therapy in medicine.”

This process will generate huge quantities of data and researchers from the University of Dundee will provide specialised software solutions for managing the big data involved in applying precision medicine. The Dundee team, led by Professor Angus Lamond, has pioneered proteomics research and software developments for the analysis of disease mechanisms.

Professor Whetton added: “Working with Professor Lamond and his world-leading team will give us a new ability to manage and analyse the huge amounts of data we will be generating. This offers exciting new opportunities for improving UK healthcare and to progress this field of research at pace and scale.”

The new collaboration combines the expertise of Swag直播 and Dundee to advance research on psoriasis, arthritis, cancer, lupus and other diseases and Professor Lamond, Director of the Laboratory of Quantitative Proteomics at the University of Dundee, believes that the better use of data can deliver significant benefits in these and other illnesses.

He said: “Efficient new computational tools are critical for handling the big data now emerging from biomedical and clinical laboratories.

“We are very enthusiastic at the prospect of working with Professor Whetton and his colleagues to help deliver the healthcare benefits from using proteomics and other innovative technologies.”

, Vice-President and Dean of at Swag直播 said: “Through ground-breaking collaboration that brings some of the UKs best scientists and resources on proteomics into focus on key disease areas, our universities are changing not only how we deliver scientific advances but also faster and greater impact on disease.”

Research in Swag直播 has identified mutations in lung cancer that is key to tumour growth, offering a new way to differentiate and treat some patients with the disease.

Non-small cell lung cancer (NSCLC) makes up around 8 in 10 cases of lung cancer but the outlook is bleak for many patients, who are often diagnosed at a late stage. For some there is the promise of targeted ‘smart’ drugs, but scientists have so far struggled to identify which targets to hit in the majority of patients.

Despite an ever-increasing amount of genetic data revealing a host of mutations in NSCLC cells, there is much work to do in order to pinpoint which are vital for tumour survival.

The team from has focused on a pair of genes known as ABL1 and ABL2, which are mutated or amplified in up to 10% of lung cancer cases.

, who led the study, said: “Drugs that block the activity of the ABL proteins have been used to successfully treat leukaemia patients, where ABL is overactive. However, until now, the role of ABL1 and ABL2 in other cancer types hasn’t really been explored.”

His group looked at lung cancer cells in the lab and showed that mutations in ABL1, but not ABL2, were necessary for their survival. By using an ABL inhibitor – imatinib – they could block tumour growth in cancer cells that harboured an ABL1 mutation.

“Drugs like imatinib are already commercially available. This means that we now have an extra ready-made tool for the treatment of lung cancer – we just need to identify which patients will benefit by doing some additional tests,” added Dr Brognard.

Paper entitled ‘’ E Testoni et al. (2016) EMBO Molecular Medicine DOI: 10.15252/emmm.201505456

Cancer is one of Swag直播’s - examples of pioneering discoveries, interdisciplinary collaboration and cross-sector partnerships that are tackling some of the biggest questions facing the planet.

Scientists at Swag直播 have discovered a new genetic syndrome of obesity, over-eating, mental and behavioural problems in six families, from across the world.

, Clinical Senior Lecturer at , who led the study, explained: “Our team has identified that this new syndrome is caused by a small deletion on chromosome 6 that affects the function of hypothalamus, a region of the brain that plays a number of important roles in the body.”

Working in collaboration with Dr Eric Glasgow of the Georgetown University Medical Center in Washington D.C., the two teams used zebrafish models to study the consequences of chromosome 6 deletion and showed that the deletion has an effect on specific cells in the hypothalamus that produce a hormone called oxytocin.

This explains why sufferers are often severely obese, find it difficult to control their appetites and are prone to mood swings and being withdrawn.

The study, published in the latest issue of the American Journal of Human Genetics represents an important step in our understanding of how the hypothalamus and oxytocin control appetite and behaviour. Dr Banka, who is also a Consultant Clinical Geneticist at , said: “This finding demonstrates the power of human genetic study of rare conditions.”

Although at an early stage, the researchers hope that the findings will help form part of a picture of how the hypothalamus works and may lead to new treatments in the future.

The paper, .

DOI: 10.1016/j.ajhg.2015.12.014

New research from Swag直播 and the Babraham Institute has revealed how gaps between genes interact to influence the risk of acquiring diseases such as arthritis and type 1 diabetes.

Writing in Nature Communications, the scientists show gap regions within the folds of DNA that have a crucial effect on turning genes on and controlling their expression, actually physically interact with genes not previously thought to be important in disease.  Many of these genes are now thought to increase the risk of people developing diseases such as arthritis, psoriasis and type 1 diabetes.

Lead researcher from Swag直播 said: “It used to be the case that researchers would seek to identify a gene which caused a particular disease by a ‘nearest gene’ approach, to the gap regions.
 

“The reality is much more complex than that.  Not only do the gaps between genes have an effect but, as we show in the new study, the gaps don’t necessarily affect the nearest gene – they can work over longer distances to turn distant genes on or off.”

This process is caused by the folding of the two metre DNA to make it fit within a cell. This folding, brings gap regions close to the ‘more important’ regions, and therefore controls the levels of genes. In certain parts of the folded DNA, regions that increase risk to different diseases can ‘meet’ at the same gene.

The findings also open up the possibility that some genes may be increasing the risk of more than one disease, depending on how they are regulated by the gaps and from where in the DNA structure.  This knowledge could lead to greater understanding of the diseases and insights into potential treatments. 

The next steps in the research are to identify more of these complex interactions and in different types of cell in order to build a more complete picture of how genes and gaps interact to increase disease risk. 

Dr Eyre added: “This research shows just how complicated the interactions within our cells are – much more so than was previously thought.  However, by gaining a better understanding of this process we open up many more possibilities for research into cures and treatments in the years ahead.”

The research was funded through and a Fellowship and has had support from The National Institute for Health Research (NIHR) . Researchers from the University of Cambridge and the Babraham Institute also contributed to the work.

The paper, ‘Capture Hi-C reveals novel candidate genes and complex long-range interactions with related autoimmune risk loci’ was published in the journal . DOI:

The work could be used to educate better rice grain improvement projects, something that may prove crucial with growing environmental concerns.

The study focused on 3 major types of rice: the long-grain Indica which is non-sticky and mainly found in tropical lowland Asia; Japonica a short-grain rice that produces sticky rice, like the one in sushi and Aus, the drought-tolerant variety that grows in Bangladesh.

Before this study, researchers had thought rice may have been domesticated once or perhaps twice. Scientists had looked at Japonica and Indica because they have had the longest history of cultivation. Some argue that Japonica came first around 10,000 years ago and that Indica emerged as a hybrid form of it a little later. Others contend that both Japonica and Indica have separate domestication events.

However, new analysis from Professor Terry Brown, Dr Peter Civan and colleagues add a third domestication event to the mix by showing evidence that Aus was also domesticated separately in a region from India to Bangladesh.

The team looked at genetic data from 446 samples of different wild rice to see how far back Aus had a commonality with them compared to when other types of rice did. Specifically, they looked at ‘domestication sweeps’ which are specific parts of the genome that differ from wild types and that scientists believe were chosen by early farmers because they had a great advantage to growing more grain. For example, the sweep region includes the ability for rice plants to grow more vertically and so can be planted more densely.

Brown and the team say that the genetic evidence that they have collected shows that these advantageous genes were present in a number of wild type rice varieties that were widely distributed across South Asia. It is therefore possible for farmers from three separate locations to select these wild types with the ideal genes and begin to cultivate them.

But why the big deal about rice? Well rice is thought to have brought about the great civilisations in Asia and led the way for large-scale agriculture to take place. Rice acted as a reliable food source and so large numbers of humans could gather to form large villages and settlements. Understanding how rice was domesticated would allow scientists to get a better understanding of how civilisations grew and moved across Asia.

Professor Brown concludes: "Our conclusions are in accord with archaeological evidence that suggests widespread origins of rice cultivation. We therefore anticipate that our results will stimulate a more productive collaboration between genetic and archaeological studies of rice domestication."

Scientists have discovered the cells driving the annual body clock in animals which adapts their body to the changing seasons.

The BBSRC team from The Universities of Swag直播 and Edinburgh reveal that cells in a structure called the ‘pars tuberalis’- which is situated in the pituitary gland – there are specialised cells that respond according how much daylight there is, providing an internal genetic calendar for the animal.

The activity of these “calendar cells” changes dramatically over the year, with different proteins produced in winter or summer months. The switching between proteins in calendar cells is what drives the seasonal cycle in sheep and other mammals.

The findings, published in the journal Current Biology, advance our understanding of how the environment affects animals – but could also be relevant to humans.

Lead Author Professor Andrew Loudon from Swag直播 said: “Scientists have long puzzled over how many animals seem to change their physiology according to the seasons.

 “Animals need to change their physiology to predict the changing environment and increase their chances for survival.

 “For example, some animals hibernate through the winter and others, including sheep, will time mating to the winter so they can give birth in the spring – when more food is available.

 “Now we have a much stronger understanding about how the body’s so-called circannual clock regulates this process.”

The study took three years to complete and involved analysis of how sheep respond to seasonal changes in daylength.

Dr Shona Wood, Research Associate from Swag直播 said: “A similar structure can be found in most animals - including humans.

“Scientists once believed that humans did not show seasonal adaptations, but more recent research has found that this may not be the case and in fact there is seasonal variation in protection against infectious disease.

“Our study gives more increases our understanding of how this may work.

Professor Dave Burt from Edinburgh said: "The seasonal clock found in sheep is likely to be the same in all vertebrates, or at least, contains the same parts list. The next step is to understand how our cells record the passage of time ."

A group of scientists led by Dr Kara Hoover of the University of Alaska Fairbanks and including Professor Matthew Cobb of Swag直播, has studied how our sense of smell has evolved, and has even reconstructed how a long-extinct human relative would have been able to smell.

The sense of smell plays a decisive role in human societies, as it is linked to our taste for food, as well as our identification of pleasant and unpleasant substances. 

We have about 4 million smell cells in our noses, divided into about 400 different types. There is tremendous genetic variability within and between populations for our ability to detect odours. Each smell cell carries just one type of receptor or 'lock' on it - the smell floats through the air, fits into the 'lock' and then activates the cell.

Most receptors can detect more than one smell, but one, called OR7D4, enables us to detect a very specific smell called androstenone, which is produced by pigs and is found in boar meat. People with different DNA sequences in the gene producing the OR7D4 receptor respond differently to this smell - some people find it foul, some sweet, and others cannot smell it at all. People's responses to androstenone can be predicted by their OR7D4 DNA sequence, and vice versa.

from Swag直播’s and the other researchers studied the DNA that codes for OR7D4 from over 2,200 people from 43 populations around the world, many of them from indigenous groups. They found that different populations tend to have different gene sequences and therefore differ in their ability to smell this compound.

For example, they found that populations from Africa - where humans come from - tend to be able to smell it, while those from the northern hemisphere tend not to. This shows that when humans first evolved in Africa, they would have been able to detect this odour.

Statistical analysis of the frequencies of the different forms of the OR7D4 gene from around the world suggested that the different forms of this gene might have been subject to natural selection.

One possible explanation of this selection is that the inability to smell androstenone was involved in the domestication of pigs by our ancestors - andostroneone makes pork from uncastrated boars taste unpleasant to people who can smell it. Pigs were initially domesticated in Asia, where genes leading to a reduced sensitivity to androstenone have a high frequency.

The group also studied the OR7D4 gene in the ancient DNA from two extinct human populations, Neanderthals and the Denisovans, whose remains were found at the same site in Siberia, but who lived tens of thousands of years apart.

The group found that Neanderthal OR7D4 DNA was like our own - they would have been able to smell androstenone. The Denisovans are a mysterious group of our extinct relatives - we do not know what they looked like, and they are known from only one tooth and a finger bone, from different individuals.

Their DNA showed a unique mutation, not seen in humans or Neanderthals, that changed the structure of the OR7D4 receptor.

Team-member Hiroaki Matsunami at Duke University in the USA reconstructed the Denisovan OR7D4 and studied how this tiny part of a long-extinct nose responded to androstenone. It turned out that despite the mutation, the Denisovan nose functioned like our own. Both of our close relatives, like our early human ancestors, would have been able to detect this strange smell.

This research shows how global studies of our genes can give insight into how our taste for different foods may have been influenced by variation in our ability to smell, and, excitingly, show that it is possible to see back into deep evolutionary time and reconstruct the sensory world of our distant ancestors.

The research was carried out by scientists from the University of Alaska Fairbanks, State University of New York, Duke University and Swag直播, and is published in the journal Chemical Senses.

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