̽��ֱ�� of Cambridge - Patrick Chinnery

Ten Cambridge scientists elected as Fellows of the Royal Society 2024

Anonymous — Thu, 16 May 2024 08:51:02 +0000

̽��ֱ��Royal Society is a self-governing Fellowship of many of the world’s most distinguished scientists drawn from all areas of science, engineering and medicine.

̽��ֱ��Society’s fundamental purpose, as it has been since its foundation in 1660, is to recognise, promote and support excellence in science and to encourage the development and use of science for the benefit of humanity.

This year, over 90 researchers, innovators and communicators from around the world have been elected as Fellows of the Royal Society for their substantial contribution to the advancement of science. Nine of these are from the ̽��ֱ�� of Cambridge.

Sir Adrian Smith, President of the Royal Society said: “I am pleased to welcome such an outstanding group into the Fellowship of the Royal Society.

“This new cohort have already made significant contributions to our understanding of the world around us and continue to push the boundaries of possibility in academic research and industry.

“From visualising the sharp rise in global temperatures since the industrial revolution to leading the response to the Covid-19 pandemic, their diverse range of expertise is furthering human understanding and helping to address some of our greatest challenges. It is an honour to have them join the Fellowship.”

̽��ֱ��Fellows and Foreign Members join the ranks of Stephen Hawking, Isaac Newton, Charles Darwin, Albert Einstein, Lise Meitner, Subrahmanyan Chandrasekhar and Dorothy Hodgkin.

̽��ֱ��new Cambridge fellows are:

Professor Sir John Aston Kt FRS

Aston is the Harding Professor of Statistics in Public Life at the Statistical Laboratory, Department of Pure Mathematics and Mathematical Statistics, where he develops techniques for public policy and improves the use of quantitative methods in public policy debates.

From 2017 to 2020 he was the Chief Scientific Adviser to the Home Office, providing statistical and scientific advice to ministers and officials, and was involved in the UK’s response to the Covid pandemic. He was knighted in 2021 for services to statistics and public policymaking, and is a Fellow of Churchill College.

Professor Sarah-Jayne Blakemore FBA FMedSci FRS

Blakemore is the Professor of Psychology and Cognitive Neuroscience, Department of Psychology, and leader of the Developmental Cognitive Neuroscience Group. Her research focuses on the development of social cognition and decision making in the human adolescent brain, and adolescent mental health.

Blakemore has been awarded several national and international prizes for her research, and is a Fellow of the British Academy, the American Association of Psychological Science and the Academy of Medical Sciences.

Professor Patrick Chinnery FMedSci FRS

Chinnery is Professor of Neurology and head of the ̽��ֱ��’s Department of Clinical Neurosciences, and a Fellow of Gonville & Caius College. He was appointed Executive Chair of the Medical Research Council last year, having previously been MRC Clinical Director since 2019.

His principal research is the role of mitochondria in human disease and developing new treatments for mitochondrial disorders. Chinnery is a Wellcome Principal Research Fellow with a lab based in the MRC Mitochondrial Biology Unit and jointly chairs the NIHR BioResource for Translational Research in Common and Rare Diseases. He is a Fellow of the Academy of Medical Sciences.

Professor Rebecca Fitzgerald OBE FMedSci FRS

Fitzgerald is Professor of Cancer Prevention in the Department of Oncology and the inaugural Director of the ̽��ֱ��’s new Early Cancer Institute, which launched in 2022. She is a Fellow of Trinity College.

Her pioneering work to devise a first-in-class, non-endoscopic capsule sponge test for identifying individuals at high risk for oesophageal cancer has won numerous prizes, including the Westminster Medal, and this test is now being rolled out in the NHS and beyond by her spin-out Cyted Ltd.

Professor David Hodell FRS

Hodell is the Woodwardian Professor of Geology and Director of the Godwin Laboratory for Palaeoclimate Research in the Department of Earth Sciences, and a Fellow of Clare College.

A marine geologist and paleoclimatologist, his research focuses on high-resolution paleoclimate records from marine and lake sediments, as well as mineral deposits, to better understand past climate dynamics. Hodell is a fellow of the American Geophysical Union and the American Association for the Advancement of Science. He has received the Milutin Milankovic Medal.

Professor Eric Lauga FRS

Lauga is Professor of Applied Mathematics in the Department of Applied Mathematics and Theoretical Physics, where his research is in fluid mechanics, biophysics and soft matter. Lauga is the author, or co-author, of over 180 publications and currently serves as Associate Editor for the journal Physical Review Fluids.

He is a recipient of three awards from the American Physical Society: the Andreas Acrivos Dissertation Award in Fluid Dynamics, the François Frenkiel Award for Fluid Mechanics and the Early Career Award for Soft Matter Research. He is a Fellow of the American Physical Society and of Trinity College.

Professor George Malliaras FRS

Malliaras is the Prince Philip Professor of Technology in the Department of Engineering, where he leads a group that works on the development and translation of implantable and wearable devices that interface with electrically active tissues, with applications in neurological disorders and brain cancer.

Research conducted by Malliaras has received awards from the European Academy of Sciences, the New York Academy of Sciences, and the US National Science Foundation among others. He is a Fellow of the Materials Research Society and of the Royal Society of Chemistry.

Professor Lloyd Peck FRI FRSB FRS

Peck is a marine biologist at the British Antarctic Survey and a fellow at Wolfson College, Cambridge.

He identified oxygen as a factor in polar gigantism and identified problems with protein synthesis as the cause of slow development and growth in polar marine species. He was awareded a Polar Medal in 2009, the PLYMSEF Silver medal in 2015 and an Erskine Fellowship at the ̽��ֱ�� of Canterbury, Christchurch in 2016-2017.

Professor Oscar Randal-Williams FRS

Randal-Williams is the Sadleirian Professor of Pure Mathematics in the Department of Pure Mathematics and Mathematical Statistics.

He has received the Whitehead Prize from the London Mathematical Society, a Philip Leverhulme Prize, the Oberwolfach Prize, the Dannie Heineman Prize of the Göttingen Academy of Sciences and Humanities, and was jointly awarded the Clay Research Award.

Randal-Williams is one of two managing editors of the Proceedings of the London Mathematical Society, and an editor of the Journal of Topology.

Professor Mihaela van der Schaar FRS

Van der Schaar is the John Humphrey Plummer Professor of Machine Learning, Artificial Intelligence and Medicine in the Departments of Applied Mathematics and Theoretical Physics, Engineering and Medicine.

She is the founder and director of the Cambridge Centre for AI in Medicine, and a Fellow at ̽��ֱ��Alan Turing Institute. Her work has received numerous awards, including the Oon Prize on Preventative Medicine, a National Science Foundation CAREER Award, and the IEEE Darlington Award.

Van der Schaar is credited as inventor on 35 US patents, and has made over 45 contributions to international standards for which she received three ISO Awards. In 2019, a Nesta report declared her the most-cited female AI researcher in the UK.

Ten outstanding Cambridge researchers have been elected as Fellows of the Royal Society, the UK’s national academy of sciences and the oldest science academy in continuous existence.

Royal Society

̽��ֱ��Royal Society in central London

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

Yes

Over 20,000 people join search for new dementia treatments

cjb250 — Tue, 14 May 2024 09:00:00 +0000

Using the resource, scientists have already been able to show for the first time that two important bodily mechanisms – inflammation and metabolism – play a role in the decline in brain function as we age.

By 2050, approximately 139 million people are expected to be living with dementia worldwide. In the UK, in 2022, UK Prime Minister launched the Dame Barbara Windsor Dementia Mission, part of the government’s commitment to double increase research funding for dementia.

Although there has been recent progress developing drugs that slow down progression of the disease, the two leading treatments only have a small effect, and the vast majority of new approaches that work in animal studies fail when it comes to patient clinical trials.

One explanation for these failures is that the drugs are tested in people who already have memory loss – and by this point, it may be too late to stop or reverse the disease. Hence, there is an urgent need to understand what is going on before people develop symptoms at the very early stages of disease, and to test new treatments before people come to their doctor with cognitive problems. This approach requires a large cohort of participants willing to be recalled for clinical and experimental studies of cognitive decline.

Today, writing in the journal Nature Medicine, scientists led by the ̽��ֱ�� of Cambridge in partnership with the Alzheimer’s Society report how they have recruited 21,000 people aged 17-85 to the Genes and Cognition Cohort within the National Institute for Health and Care Research (NIHR) BioResource.

̽��ֱ��NIHR BioResource was established in 2007 to recruit volunteers keen to engage in experimental medicine and clinical trials across the whole of medicine. Approximately half of its participants are recruited to disease specific cohorts, but the other half are from the general public, and detailed information about their genetics and their physical makeup has been collected. They have all given their consent to be contacted about future research studies.

For the Genes and Cognition Cohort, researchers used a combination of cognitive tests and genetic data, combined with other health data and demographic information, to enable the first at-scale study of cognitive changes. This will allow the team to recruit participants for studies of cognitive decline and new treatments for this.

For example, a pharmaceutical company with a promising new drug candidate to slow the cognitive decline could recruit people through the BioResource based on their profile and invite them to join in the clinical trial. Having a baseline measurement for their cognitive performance will allow scientists to observe whether the drug slows their expected cognitive decline.

Professor Patrick Chinnery from the Department of Clinical Neurosciences at the ̽��ֱ�� of Cambridge and co-Chair of the NIHR BioResource, who has led the project, said: “We’ve created a resource that is unmatched anywhere else in the world, recruiting people who are not showing any signs of dementia rather than people already having symptoms. It will allow us to match individuals to particular studies and speed up the development of much-needed new drugs to treat dementia.

“We know that over time our cognitive function decreases, so we’ve plotted out the expected trajectory of various different cognitive functions over our volunteers’ life course according to their genetic risk. We’ve also asked the question, ‘What are the genetic mechanisms that predispose you to slow or fast cognitive decline as you age?’.”

Using the research, the team have identified two mechanisms that appear to affect cognition as we age and could serve as potential targets to slow down cognitive decline and thereby delay the onset of dementia. ̽��ֱ��first of these is inflammation, with immune cells specific to the brain and central nervous system – known as microglia – causing gradual deterioration of the brain and hence its ability to perform key cognitive functions. ̽��ֱ��second mechanism relates to metabolism – in particular, how carbohydrates are broken down in the brain to release energy.

Professor Chinnery added: “Cognitive decline is a natural process, but when it drops below a particular threshold, that’s when there’s a problem – that is when we would diagnose dementia. Anything that slows that decline will delay when we drop below that threshold. If you could put off the onset of dementia from 65 to 75 or even 85, it would make a huge difference at an individual and at a population level.”

Dr Richard Oakley, Associate Director of Research and Innovation at Alzheimer’s Society, said: “This exciting study, funded by Alzheimer’s Society, is an important step in helping us to better understand how the diseases that cause dementia begin, and will aid in the development of new treatments that target the early stages of these diseases.

“ ̽��ֱ��data, from over 20,000 volunteers, helps us to better understand the connection between participants’ genes and cognitive decline and allows for further ground-breaking analysis in future.

“One in three people born in the UK today will go on to develop dementia in their lifetime but research will beat dementia. We need to make it a reality sooner through more funding, partnership working and people taking part in dementia research.”

For further information about how you can join the BioResource and contribute to studies like this one and many others, please visit bioresource.nihr.ac.uk.

̽��ֱ��research was carried out in collaboration with the Medical Research Council Biostatistics Unit and was supported by the Alzheimer’s Society and the NIHR BioResource. ̽��ֱ��researchers were also supported by Wellcome and the Medical Research Council.

Reference
Rahman, MS et al. Dynamics of cognitive variability with age and its genetic underpinning in NIHR BioResource Genes and Cognition Cohort participants. Nat Med; 14 May 2024; DOI: 10.1038/s41591-024-02960-5

More than 20,000 volunteers have been recruited to a resource aimed at speeding up the development of much-needed dementia drugs. ̽��ֱ��cohort will enable scientists in universities and industry to involve healthy individuals who may be at increased risk of dementia in clinical trials to test whether new drugs can slow the decline in various brain functions including memory and delay the onset of dementia.

We’ve created a resource that is unmatched anywhere else in the world, recruiting people who are not showing any signs of dementia rather than people already having symptoms

Patrick Chinnery

Halfpoint Images (Getty Images)

Smiling elderly woman speaking to a healthcare worker

Yes

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

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

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

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

LifeArc Centre for Rare Mitochondrial Diseases

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

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

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

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

LifeArc Centre for Rare Respiratory Diseases

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

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

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

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

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

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

Adapted from a press release from LifeArc

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

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

Patrick Chinnery

Alexander_Safonov (Getty)

Woman inhaling from a mask nebulizer

Yes

Clinical trial underway to treat ultra-rare genetic disease with possible link to leader of mutiny on the Bounty

jg533 — Thu, 21 Mar 2024 09:00:00 +0000

A clinical trial to look at repurposing the UK-licensed medicine deferiprone for patients with the ultra-rare genetic disease neuroferritinopathy has launched today at the ̽��ֱ�� of Cambridge.

Neuroferritinopathy is a progressive and incurable brain disorder caused by changes in a gene that produces a specific protein - ferritin light chain protein. This change leads to the build-up of iron in the brain. ̽��ֱ��disease usually appears in middle-aged adults and causes severe symptoms that impact on day-to-day life, eventually resulting in the loss of speech and swallowing. There are currently no effective treatments.

Funded by LifeArc, the new randomised placebo-controlled trial - DefINe - will be led by Professor Patrick Chinnery from the Department of Clinical Neurosciences. It aims to stop the progression of the disease by reducing the iron accumulation in the brain with an existing drug called deferiprone. Deferiprone is an affordable oral tablet that is already licensed for use in the UK to reduce iron levels in blood conditions like thalassemia. If successful, the trial could also open the possibility of deferiprone being used for other neurodegenerative conditions linked with build-up of iron the brain.

Professor Chinnery said: “Neuroferritinopathy leads to severe disability and currently has no cure. ̽��ֱ��DefINe trial will show whether we can stop the disease in its tracks by pulling iron out of the brain using a well-known medicine called deferiprone.

“By funding this study, LifeArc has given the first hope of a treatment for affected families. If successful, the trial will open the possibility of using a similar approach for other neurodegenerative conditions linked to the build-up of iron in the brain, including Parkinson’s disease.”

Neuroferritinopathy affects approximately 100 patients worldwide. Initial discovery of the condition came when a surprising number of individuals diagnosed found to live in the Lake District in Cumbria experienced similar symptoms with a series of incorrect diagnoses. Research into the ancestry of these families by Professor John Burn, a clinical geneticist at Newcastle Hospitals NHS Foundation Trust, discovered the genetic commonality and also found an interesting potential link to the past.

Professor Burn found that a rare mutation caused the progression of the condition and almost all the known cases were likely to be descended from the same ancestor. He traced it back to the 18th Century in Cockermouth in Cumbria and families with the surname Fletcher. Professor Burn suggested they could have shared common ancestry with Fletcher Christian (Fletcher being his surname), known for leading the mutiny on the Bounty in April 1789, given he was also from the region.

̽��ֱ��DefINe trial will involve 40 patients taking the drug for a year, who will undergo state-of-the-art 7T magnetic resonance imaging (MRI) scanning to monitor the iron levels in the brain throughout. ̽��ֱ��evidence collected will form the basis of an application for licensing in the UK under ‘Exceptional Circumstances’, which is often used for rare conditions where the number of people affected is low. This means, if the trial is successful the drug could go on to benefit all people with the condition more quickly.

Samantha Denison, a patient hoping to participate in the trial, said: “It came as such a surprise to be informed of the trial and to learn that we have not been forgotten about. To have the chance to be involved in the trial gives me such hope. If it can help to slow or stop the condition progressing, that would be a huge relief. Just to know that by taking part we could also be helping future generations, is amazing.”

LifeArc has contributed £750,000 to the project and Lipomed, a Swiss life sciences company, has offered to provide both a cost-effective generic form of deferiprone, Deferiprone Lipomed, and a placebo to the trial – a Gift in Kind worth £250,000.

Dr Catriona Crombie, Head of LifeArc’s Rare Disease Translational Challenge, said: “Drug repurposing trials like this are an increasingly effective way of taking treatments that have already been approved and applying them to new conditions and diseases. This will help unlock new treatments for conditions that currently have few, if any, available."

Dr Chantal Manz, Chief Scientific Officer Lipomed AG, Switzerland, said: “Lipomed is very excited to support this promising study concept in patients with neuroferritinopathy, by providing deferiprone 500 mg film-coated tablets and matching placebo tablets. We recognise the unmet clinical need and the potentially significant benefit of this orally active iron chelator. Deferiprone is able to penetrate the blood-brain barrier and may reduce cerebral iron accumulation in patients with this extremely rare, but devastating genetic neurodegenerative disorder, for which no alternative treatments are available.”

Adapted from a press release by LifeArc.

If successful, the trial will open the possibility of using a similar approach for other neurodegenerative conditions linked to the build-up of iron in the brain, including Parkinson’s disease.

Patrick Chinnery

Patrick Chinnery looks at brain scans

Yes

Leading Cambridge neuroscientist appointed as Executive Chair of Medical Research Council

cjb250 — Tue, 22 Aug 2023 09:40:00 +0000

̽��ֱ��Secretary of State for Science, Innovation and Technology, Michelle Donelan, has appointed Professor Patrick Chinnery as the next Executive Chair of the MRC.

Michelle Donelan said: “Professor Chinnery brings a wealth of experience as a practicing clinician and an already established and valued member of the Medical Research Council.

“By heading up one of the UK’s key public funding bodies for medical research, he will spearhead delivery of high-quality training and fellowships for researchers and funding for life-changing discoveries that are so crucial to our country’s health and wellbeing.

“I also pay tribute to Professor John Iredale for his work as interim Executive Chair and thank him for his invaluable service.”

Professor Chinnery is currently the MRC’s Director of Clinical Sciences and Professor of Neurology at Cambridge. He is also an Honorary Consultant Neurologist at Cambridge ̽��ֱ�� Hospitals NHS Trust. Professor Chinnery’s key research interest concerns the role of mitochondria in human disease and investigating ways to develop new treatments for mitochondrial disorders.

UKRI Chief Executive Dame Ottoline Leyser said: "Professor Chinnery is an exceptional leader who will play a key role in the continued development of UKRI and the Medical Research Council, ensuring it maintains its pivotal role in driving excellence in the biomedical and health sciences.

"He brings a great breadth of experience from across the medical sciences combined with a deep knowledge of the organisation from his time as MRC’s Director of Clinical Sciences. I look forward to continuing to work with him in his new role.

"I would also like to take this opportunity to express my profound thanks to Professor John Iredale for his superb service and leadership as MRC's interim Executive Chair, on which Professor Chinnery will build."

Professor Chinnery said: “Opportunities to advance human health through research have never been greater, and the UK is in a very strong position globally. It will be a real privilege to lead the MRC at this exciting time, working with colleagues in UKRI and across the sector to deliver scientific and clinical impact.”

As MRC Executive Chair, Professor Chinnery will oversee the Council’s full range of funding programmes and be responsible for its annual core budget alongside infrastructure and other cross-cutting UKRI funding allocated to the MRC. He will be responsible for MRC’s portfolio of institutes as well as for the Council’s wider role in providing training and support for the UK medical research community.

Professor Chinnery will also join the other UKRI Executive Chairs as a member of the UKRI senior leadership team and will work closely with them, UKRI’s Chief Executive and the UKRI Board to collectively manage and oversee UKRI’s strategy, funding programmes and infrastructure. He will succeed the current interim Executive Chair of MRC, Professor John Iredale and is expected to start in October.

Professor Anne Ferguson-Smith, Pro-Vice Chancellor for Research at the ̽��ֱ�� of Cambridge, welcomed the appointment. She said: “Many congratulations to Patrick on his appointment as Executive Chair of the MRC. In addition to being a world-leading active researcher in mitochondrial disease genetics, Patrick brings a wealth of MRC experience to this role, most recently as its Clinical Director and I know he has a strong commitment to the development of our next generation of biomedical researchers.

“These are important times for the MRC as it continues to invest in fundamental discovery research in the life sciences, experimental medicine and the translation of both to the clinic. His is an excellent appointment and we wish Patrick all the very best as he takes the helm at the MRC.”

Professor Patrick Chinnery, Head of the Department of Clinical Neurosciences at the ̽��ֱ�� of Cambridge, has been appointed as the new Executive Chair of the Medical Research Council (MRC).

Opportunities to advance human health through research have never been greater, and the UK is in a very strong position globally. It will be a real privilege to lead the MRC at this exciting time

Patrick Chinnery

̽��ֱ�� of Cambridge

Professor Patrick Chinnery

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

Yes

New route to evolution: how DNA from our mitochondria gets into our genomes

cjb250 — Wed, 05 Oct 2022 15:00:50 +0000

In a study published today in Nature, researchers at the ̽��ֱ�� of Cambridge and Queen Mary ̽��ֱ�� of London show that mitochondrial DNA also appears in some cancer DNA, suggesting that it acts as a sticking plaster to try and repair damage to our genetic code.

Mitochondria are tiny ‘organelles’ that sit within our cells, where they act like batteries, providing energy in the form of the molecule ATP to power the cells. Each mitochondrion has its own DNA – mitochondrial DNA – that is distinct to the rest of the human genome, which is comprised of nuclear DNA.

Mitochondrial DNA is passed down the maternal line – that is, we inherit it from our mothers, not our fathers. However, a study published in PNAS in 2018 from researchers at the Cincinnati Children’s Hospital Medical Center in the USA reported evidence that suggested some mitochondrial DNA had been passed down the paternal line.

To investigate these claims, the Cambridge team looked at the DNA from over 11,000 families recruited to Genomics England’s 100,000 Genomes Project, searching for patterns that looked like paternal inheritance. ̽��ֱ��Cambridge team found mitochondrial DNA ‘inserts’ in the nuclear DNA of some children that were not present in that of their parents. This meant that the US team had probably reached the wrong conclusions: what they had observed were not paternally-inherited mitochondrial DNA, but rather these inserts.

Now, extending this work to over 66,000 people, the team showed that the new inserts are actually happening all the time, showing a new way our genome evolves.

Professor Patrick Chinnery, from the Medical Research Council Mitochondrial Biology Unit and Department of Clinical Neurosciences at the ̽��ֱ�� of Cambridge, explained: “Billions of years ago, a primitive animal cell took in a bacterium that became what we now call mitochondria. These supply energy to the cell to allow it to function normally, while removing oxygen, which is toxic at high levels. Over time, bits of these primitive mitochondria have passed into the cell nucleus, allowing their genomes to talk to each other.

“This was all thought to have happened a very long time ago, mostly before we had even formed as a species, but what we've discovered is that that’s not true. We can see this happening right now, with bits of our mitochondrial genetic code transferring into the nuclear genome in a measurable way.”

̽��ֱ��team estimate that mitochondrial DNA transfers to nuclear DNA in around one in every 4,000 births. If that individual has children of their own, they will pass these inserts on – the team found that most of us carry five of the new inserts, and one in seven of us (14%) carry very recent ones. Once in place, the inserts can occasionally lead to very rare diseases, including a rare genetic form of cancer.

It isn’t clear exactly how the mitochondrial DNA inserts itself – whether it does so directly or via an intermediary, such as RNA – but Professor Chinnery says it is likely to occur within the mother’s egg cells.

When the team looked at sequences taken from 12,500 tumour samples, they found that mitochondrial DNA was even more common in tumour DNA, arising in around one in 1,000 cancers, and in some cases, the mitochondrial DNA inserts actually causes the cancer.

“Our nuclear genetic code is breaking and being repaired all the time,” said Professor Chinnery. “Mitochondrial DNA appears to act almost like a Band-Aid, a sticking plaster to help the nuclear genetic code repair itself. And sometimes this works, but on rare occasions if might make things worse or even trigger the development of tumours.”

More than half (58%) of the insertions were in regions of the genome that code for proteins. In the majority of cases, the body recognises the invading mitochondrial DNA and silences it in a process known as methylation, whereby a molecule attaches itself to the insert and switches it off. A similar process occurs when viruses manage to insert themselves into our DNA. However, this method of silencing is not perfect, as some of the mitochondrial DNA inserts go on to be copied and move around the nucleus itself.

̽��ֱ��team looked for evidence that the reverse might happen – that mitochondrial DNA absorbs parts of our nuclear DNA – but found none. There are likely to be several reasons why this should be the case.

Firstly, cells only have two copies of nuclear DNA, but thousands of copies of mitochondrial DNA, so the chances of mitochondrial DNA being broken and passing into the nucleus are much greater than the other way around.

Secondly, the DNA in mitochondria is packaged inside two membranes and there are no holes in the membrane, so it would be difficult for nuclear DNA to get in. By contrast, if mitochondrial DNA manages to get out, holes in the membrane surrounding nuclear DNA would allow it pass through with relative ease.

Professor Sir Mark Caulfield, Vice Principal for Health at Queen Mary ̽��ֱ�� of London, said: “I am so delighted that the 100,000 Genomes Project has unlocked the dynamic interplay between mitochondrial DNA and our genome in the cell’s nucleus. This defines a new role in DNA repair, but also one that could occasionally trigger rare disease, or even malignancy.”

̽��ֱ��research was mainly funded by the Medical Research Council, Wellcome, and the National Institute for Health Research.

Reference
Wei, E et al. Nuclear-embedded mitochondrial DNA sequences in 66,083 human genomes. Nature; 5 Oct 2022; DOI: 10.1038/s41586-022-05288-7

Scientists have shown that in one in every 4,000 births, some of the genetic code from our mitochondria – the ‘batteries’ that power our cells – inserts itself into our DNA, revealing a surprising new insight into how humans evolve.

Mitochondrial DNA appears to act almost like a Band-Aid, a sticking plaster to help the nuclear genetic code repair itself. And sometimes this works, but on rare occasions if might make things worse or even trigger the development of tumours

Patrick Chinnery

Dr David Furness

Mitochondria surrounded by cytoplasm

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

Yes

Licence type:

Attribution-Noncommerical

Whole genome sequencing increases diagnosis of rare disorders by nearly a third

ta385 — Thu, 04 Nov 2021 06:00:00 +0000

Mitochondrial disorders affect around 1 in 4,300 people and cause progressive, incurable diseases. They are amongst the most common inherited diseases but are difficult for clinicians to diagnose, not least because they can affect many different organs and resemble many other conditions.

Current genetic testing regimes fail to diagnose around 40% of patients, with major implications for patients, their families and the health services they use.

A new study, published in the BMJ, offers hope to families with no diagnosis, and endorses plans for the UK to establish a national diagnostic programme based on whole genome sequencing (WGS) to make more diagnoses faster.

While previous studies based on small, highly selected cohorts have suggested that WGS can identify mitochondrial disorders, this is the first to examine its effectiveness in a national healthcare system – the NHS.

̽��ֱ��study, led by researchers from the MRC Mitochondrial Biology Unit and Departments of Clinical Neuroscience and Medical Genetics at the ̽��ֱ�� of Cambridge, involved 319 families with suspected mitochondrial disease recruited through the 100,000 Genomes Project which was set up to embed genomic testing in the NHS, discover new disease genes and make genetic diagnosis available for more patients.

In total, 345 participants – aged 0 to 92 with a median age of 25 years – had their whole genome sequenced. Through different analyses, the researchers found that they could make a definite or probable genetic diagnosis for 98 families (31%). Standard tests, which are often more invasive, failed to reach these diagnoses. Six possible diagnoses (2% of the 98 families) were made. A total of 95 different genes were implicated.

Surprisingly, 62.5% of the diagnoses were actually non-mitochondrial disorders, with some having specific treatments. This happened because so many different diseases resemble mitochondrial disorders, making it very difficult to know which are which.

Professor Patrick Chinnery from the MRC Mitochondrial Biology Unit and the Department of Clinical Neurosciences at the ̽��ֱ�� of Cambridge, said:

“We recommend that whole genome sequencing should be offered early and before invasive tests such as a muscle biopsy. All that patients would need to do is have a blood test, meaning that this could be offered across the whole country in an equitable way. People wouldn’t need to travel long distances to multiple appointments, and they would get their diagnosis much faster.”

Dr Katherine Schon from the MRC Mitochondrial Biology Unit and the Departments of Clinical Neuroscience and Medical Genetics, said:

“A definitive genetic diagnosis can really help patients and their families, giving them access to tailored information about prognosis and treatment, genetic counselling and reproductive options including preimplantation genetic diagnosis or prenatal diagnosis.”

̽��ֱ��researchers made 37.5% of their diagnoses in genes known to cause mitochondrial disease. These diagnoses were nearly all unique to a particular participant family, reflecting the genetic diversity found in these disorders. ̽��ֱ��impairment of mitochondrial function tends to affect tissues with high energy demand such as the brain, the peripheral nerves, the eye, the heart and the peripheral muscles. ̽��ֱ��study offers a valuable new resource for the discovery of future mitochondrial disease genes.

̽��ֱ��majority of the team’s diagnoses (62.5%) were, however, of non-mitochondrial disorders which had features resembling mitochondrial diseases. These disorders would have been missed if the participants had only been investigated for mitochondrial disorders through muscle biopsy and/or a specific mitochondrial gene panel. These participants were living with a range of conditions including developmental disorders with intellectual disability, severe epileptic conditions and metabolic disorders, as well as heart and neurological diseases.

Chinnery said: “These patients were referred because of a suspected mitochondrial disease and the conventional diagnostic tests are specifically for mitochondrial diseases. Unless you consider these other possibilities, you won't diagnose them. Whole genome sequencing isn’t restricted by that bias.”

A small number of newly diagnosed participants are already receiving treatments as a result. ̽��ֱ��team identified potentially treatable disorders in six participants with a mitochondrial disorder and nine with a non-mitochondrial disorder, but the impact of the treatments has yet to be determined.

Chinnery said: “Diagnostic services are fragmented and unevenly distributed across the UK, and that creates major challenges for people with rare diseases and their families. By delivering a national programme based on this genome-wide approach, you can offer the same level of service to everyone."

Schon said: “If we can create a national platform of families with rare diseases, we can give them the opportunity to engage in clinical trials so we can get definitive evidence that new treatments work.”

̽��ֱ��study points out that the relatively high number of patients with probable or possible diagnoses reflects the need for greater investment into the analysis of functional effects of new genetic variants which could be the cause of disease, but it is not certain at present.

It also argues that rapid trio whole genome sequencing should be offered to all acutely unwell individuals with suspected mitochondrial disorders, so that results can help guide clinical management. Currently in the UK, this is only available for acutely unwell children.

Dr Ellen Thomas, Clinical Director and Director of Quality at Genomics England, said:

“We are very pleased to see significant research like this being enabled by data generously donated by participants of the 100,000 Genomes Project. It is clear from these results how their contributions to a rich and, importantly, secure dataset is critical in facilitating the genomic research that leads to insights like these that then have the potential to return value to the NHS and their patients. We look forward to seeing how these findings could support future care for patients with suspected mitochondrial disorders.”

Reference

KR Schon et al., ‘Use of whole genome sequencing to determine the genetic basis of suspected mitochondrial disorders: a cohort study’, BMJ (2021). DOI: 10.1136/ bmj-2021-066288

Funding

National Institute for Health Research, NHS England, Wellcome, Cancer Research UK and the Medical Research Council within UK Research and Innovation

Whole genome sequencing from a single blood test picks up 31% more cases of rare genetic disorders than standard tests, shortening the ‘diagnostic odyssey’ that affected families experience, and providing huge opportunities for future research.

A definitive genetic diagnosis can really help patients and their families

Patrick Chinnery

Belova59 via Pixabay

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Mothers can influence offspring’s height, lifespan and disease risk in unexpected ways – through their mitochondria

cjb250 — Mon, 17 May 2021 15:00:18 +0000

̽��ֱ��study, published today in Nature Genetics, found that genetic variants in the DNA of mitochondria could increase the risk of developing these conditions, as well influencing characteristics such as height and lifespan.

There was also evidence that some changes in mitochondrial DNA were more common in people with Scottish, Welsh or Northumbrian genetic ancestry, implying that mitochondrial DNA and nuclear DNA (which accounts for 99.9% of our genetic make-up) interact with each other.

Almost all of the DNA that makes up the human genome – the body’s ‘blueprint’ – is contained within the nuclei of our cells. Among other functions, nuclear DNA codes for the characteristics that make us individual as well as for the proteins that do most of the work in our bodies.

Our cells also contain mitochondria, often referred to as ‘batteries’, which provide the energy for our cells to function. They do this by converting the food that we eat into ATP, a molecule capable of releasing energy very quickly. Each of these mitochondria is coded for by a tiny amount of ‘mitochondrial DNA’. Mitochondrial DNA makes up only 0.1% of the overall human genome and is passed down exclusively from mother to child.

While errors in mitochondrial DNA can lead to so-called mitochondrial diseases, which can be severely disabling, until now there had been little evidence that these variants can influence more common diseases. Several small-scale studies have hinted at this possibility, but scientists have been unable to replicate their findings.

Now, a team at the ̽��ֱ�� of Cambridge has developed a new technique to study mitochondrial DNA and its relation to human diseases and characteristics in samples taken from 358,000 volunteers as part of UK Biobank, a large-scale biomedical database and research resource.

Dr Joanna Howson, who carried out the work while at the Department of Public Health and Primary Care at the ̽��ֱ�� of Cambridge, said: “Using this new method, we've been able to look for associations between the numerous features that have been recorded for participants of UK Biobank and see whether any correlate with mitochondrial DNA.

“Aside from mitochondrial diseases, we don’t generally associate mitochondrial DNA variants with common diseases. But what we’ve shown is that mitochondrial DNA – which we inherit from our mother – influences the risk of some diseases such as type 2 diabetes and MS as well as a number of common characteristics.”

Among those factors found to be influenced by mitochondrial DNA are: type 2 diabetes, multiple sclerosis, liver and kidney function, blood count parameters, life span and height. While some of the effects are seen more extremely in patients with rare inherited mitochondrial diseases – for example, patients with severe disease are often shorter than average – the effect in healthy individuals tends to be much subtler, likely accounting for just a few millimetres’ height difference, for example.

There are several possible explanations for how mitochondrial DNA exerts its influence. One is that changes to mitochondrial DNA lead to subtle differences in our ability to produce energy. However, it is likely to be more complicated, affecting complex biological pathways inside our bodies – the signals that allow our cells to operate in a coordinated fashion.

Professor Patrick Chinnery from the MRC Mitochondrial Biology Unit at Cambridge said: “If you want a complete picture of common diseases, then clearly you’re going to need to factor in the influence of mitochondrial DNA. ̽��ֱ��ultimate aim of studies of our DNA is to understand the mechanisms that underlie these diseases and find new ways to treat them. Our work could help identify potential new drug targets.”

Regional variations in mitochondrial DNA suggest complex interaction with nuclear DNA

Unlike nuclear DNA, which is passed down from both the mother and the father, mitochondria DNA is inherited exclusively from the mother. This suggests that the two systems are inherited independently and hence there should be no association between an individual’s nuclear and mitochondrial DNA – however, this was not what the team found.

̽��ֱ��researchers showed that certain nuclear genetic backgrounds are associated preferentially with certain mitochondrial genetic backgrounds, particularly in Scotland, Wales and Northumbria. This suggests that our nuclear and mitochondrial genomes have evolved – and continue to evolve – side-by-side and interact with each other.

One reason that may explain this is the need for compatibility. ATP is produced by a group of proteins inside the mitochondria, called the respiratory chain. There are over 100 components of the respiratory chain, 13 of which are coded for by mitochondrial DNA; the remainder are coded for by nuclear DNA. Even though proteins in the respiratory chain are being produced by two different genomes, the proteins need to physically interlock like pieces of a jigsaw.

If the mitochondrial DNA inherited by a child was not compatible with the nuclear DNA inherited from the father, the jigsaw would not fit together properly, thereby affecting the respiratory chain and, consequently, energy production. This might subtly influence an individual’s health or physiology, which over time could be disadvantageous from an evolutionary perspective. Conversely, matches would be encouraged by evolution and therefore become more common.

This could have implications for the success of mitochondrial transfer therapy – a new technique that enables scientists to replace a mother’s defective mitochondria with those from a donor, thereby preventing her child from having a potentially life-threatening mitochondrial disease.

“It looks like our mitochondrial DNA is matched to our nuclear DNA to some extent – in other words, you can’t just swap the mitochondria with any donor, just as you can’t take a blood transfusion from anyone,” explained Professor Chinnery. “Fortunately, this possibility has already been factored into the approach taken by the team at Newcastle who have pioneered this therapy.”

̽��ֱ��study was funded by Wellcome and the British Heart Foundation. Additional support was provided by the NIHR Cambridge Biomedical Research Centre.

Reference
Yonova-Doing, E et al. An atlas of mitochondrial DNA genotype-phenotype associations in the UK Biobank. Nature Genetics; 17 May 2021; DOI: 10.1038/s41588-021-00868-1

Mitochondria - the ‘batteries’ that power our cells – play an unexpected role in common diseases such as type 2 diabetes and multiple sclerosis, concludes a study of over 350,000 people conducted by the ̽��ֱ�� of Cambridge.

If you want a complete picture of common diseases, then clearly you’re going to need to factor in the influence of mitochondrial DNA

Patrick Chinnery

Bruno Nascimento

Mother and child

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