̽��ֱ�� of Cambridge - cystic fibrosis

Scientists map how deadly bacteria evolved to become epidemic

cjb250 — Thu, 04 Jul 2024 18:00:53 +0000

P. aeruginosa is responsible for over 500,000 deaths per year around the world, of which over 300,000 are associated with antimicrobial resistance (AMR). People with conditions such as COPD (smoking-related lung damage), cystic fibrosis (CF), and non-CF bronchiectasis, are particularly susceptible.

How P. aeruginosa evolved from an environmental organism into a specialised human pathogen was not previously known. To investigate this, an international team led by scientists at the ̽��ֱ�� of Cambridge examined DNA data from almost 10,000 samples taken from infected individuals, animals, and environments around the world. Their results are published today in Science

By mapping the data, the team was able to create phylogenetic trees – ‘family trees’ – that show how the bacteria from the samples are related to each other. Remarkably, they found that almost seven in ten infections are caused by just 21 genetic clones, or ‘branches’ of the family tree, that have rapidly evolved (by acquiring new genes from neighbouring bacteria) and then spread globally over the last 200 years. This spread occurred most likely as a result of people beginning to live in densely-populated areas, where air pollution made our lungs more susceptible to infection and where there were more opportunities for infections to spread.

These epidemic clones have an intrinsic preference for infecting particular types of patients, with some favouring CF patients and other non-CF individuals. It turns out that the bacteria can exploit a previously unknown immune defect in people with CF, allowing them to survive within macrophages. Macrophages are cells that ‘eat’ invading organisms, breaking them down and preventing the infection from spreading. But a previously-unknown flaw in the immune systems of CF patients means that once the macrophage ‘swallows’ P. aeruginosa, it is unable to get rid of it.

Having infected the lungs, these bacteria then evolve in different ways to become even more specialised for a particular lung environment. ̽��ֱ��result is that certain clones can be transmitted within CF patients and other clones within non-CF patients, but almost never between CF and non-CF patient groups.

Professor Andres Floto, Director of the UK Cystic Fibrosis Innovation Hub at the ̽��ֱ�� of Cambridge and Royal Papworth Hospital NHS Foundation Trust, and senior author of the study said: “Our research on Pseudomonas has taught us new things about the biology of cystic fibrosis and revealed important ways we might be able to improve immunity against invading bacteria in this and potentially other conditions.

“From a clinical perspective, this study has revealed important information about Pseudomonas. ̽��ֱ��focus has always been on how easily this infection can spread between CF patients, but we’ve shown that it can spread with worrying ease between other patients, too. This has very important consequences for infection control in hospitals, where it’s not uncommon for an infected individual to be on an open ward with someone potentially very vulnerable.

“We are incredibly lucky at Royal Papworth Hospital where we have single rooms and have developed and evaluated a new air-handling system to reduce the amount of airborne bacteria and protect all patients.”

Dr Aaron Weimann from the Victor Phillip Dahdaleh Heart & Lung Research Institute at the ̽��ֱ�� of Cambridge, and first author on the study, said: “It’s remarkable to see the speed with which these bacteria evolve and can become epidemic and how they can specialise for a particular lung environment. We really need systematic, pro-active screening of all at risk patient groups to detect and hopefully prevent the emergence of more epidemic clones.”

̽��ֱ��research was funded by Wellcome and the UK Cystic Fibrosis Trust.

Reference
Weimann, A et al. Evolution and host-specific adaptation of Pseudomonas aeruginosa. Science; 4 July 2024; DOI: 10.1126/science.adi0908

Pseudomonas aeruginosa – an environmental bacteria that can cause devastating multidrug-resistant infections, particularly in people with underlying lung conditions – evolved rapidly and then spread globally over the last 200 years, probably driven by changes in human behaviour, a new study has found.

It’s remarkable to see the speed with which these bacteria evolve and can become epidemic and how they can specialise for a particular lung environment

Aaron Weimann

engin akyurt

A man with a respirator on his face

̽��ֱ��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.

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New Heart and Lung Research Institute opens

cjb250 — Mon, 11 Jul 2022 06:31:58 +0000

A major new institute opens today, bringing together the largest concentration of scientists and clinicians in heart and lung medicine in Europe.

Ability of multi-drug resistant infection to evolve within cystic fibrosis patients highlights need for rapid treatment

cjb250 — Thu, 29 Apr 2021 18:00:25 +0000

Around one in 2,500 children in the UK is born with cystic fibrosis, a hereditary condition that causes the lungs to become clogged up with thick, sticky mucus. ̽��ֱ��condition tends to decrease life expectancy among patients.

In recent years, M. abscessus, a species of multi-drug resistant bacteria, has emerged as a significant global threat to individuals with cystic fibrosis and other lung diseases. It can cause a severe pneumonia leading to accelerated inflammatory damage to the lungs, and may prevent safe lung transplantation. It is also extremely difficult to treat – fewer than one in three cases is treated successfully.

In a study published today in Science, a team led by scientists at the ̽��ֱ�� of Cambridge examined whole genome data for 1,173 clinical M. abscessus samples taken from 526 patients to study how the organism has evolved – and continues to evolve. ̽��ֱ��samples were obtained from cystic fibrosis clinics in the UK, as well as centres in Europe, the USA and Australia.

̽��ֱ��team found two key processes that play an important part in the organism’s evolution. ̽��ֱ��first is known as horizontal gene transfer – a process whereby the bacteria pick up genes or sections of DNA from other bacteria in the environment. Unlike classical evolution, which is a slow, incremental process, horizontal gene transfer can lead to big jumps in the pathogen’s evolution, potentially allowing it to become suddenly much more virulent.

̽��ֱ��second process is within-host evolution. As a consequence of the shape of the lung, multiple versions of the bacteria can evolve in parallel – and the longer the infection exists, the more opportunities they have to evolve, with the fittest variants eventually winning out. Similar phenomena have been seen in the evolution of new SARS-CoV-2 variants in immunocompromised patients.

Professor Andres Floto, joint senior author from the Centre for AI in Medicine (CCAIM) and the Department of Medicine at the ̽��ֱ�� of Cambridge and the Cambridge Centre for Lung Infection at Royal Papworth Hospital, said: “What you end up with is parallel evolution in different parts of an individual’s lung. This offers bacteria the opportunity for multiple rolls of the dice until they find the most successful mutations. ̽��ֱ��net result is a very effective way of generating adaptations to the host and increasing virulence.

“This suggests that you might need to treat the infection as soon as it is identified. At the moment, because the drugs can cause unpleasant side effects and have to be administered over a long period of time – often as long as 18 months – doctors usually wait to see if the bacteria cause illness before treating the infection. But what this does is give the bug plenty of time to evolve repeatedly, potentially making it more difficult to treat.”

Professor Floto and colleagues have previously advocated routine surveillance of cystic fibrosis patients to check for asymptomatic infection. This would involve patients submitting sputum samples three or four times a year to check for the presence of M. abscessus infection. Such surveillance is carried out routinely in many centres in the UK.

Using mathematical models, the team have been able to step backwards through the organism’s evolution in a single individual and recreate its trajectory, looking for key mutations in each organism in each part of the lung. By comparing samples from multiple patients, they were then able to identify the key set of genes that enabled this organism to change into a potentially deadly pathogen.

These adaptations can occur very quickly, but the team found that their ability to transmit between patients was constrained: paradoxically, those mutations that allowed the organism to become a more successful pathogen within the patient also reduced its ability to survive on external surfaces and in the air – the key mechanisms by which it is thought to transmit between people.

Potentially one of the most important genetic changes witnessed by the team was one that contributed towards M. abscessus becoming resistant to nitric oxide, a compound naturally produced by the human immune system. ̽��ֱ��team will shortly begin a clinical trial aimed at boosting nitric oxide in patients’ lung by using inhaled acidified nitrite, which they hope would become a novel treatment for the devastating infection.

̽��ֱ��researchers say their findings highlight the need to treat patients with Mycobacterium abscessus infection immediately, counter to current medical practice.

Examining the DNA taken from patient samples is also important in helping understand routes of transmission. Such techniques are used routinely in Cambridge hospitals to map the spread of infections such as MRSA and C. difficile – and more recently, SARS-CoV-2. Insights into the spread of M. abscessus helped inform the design of the new Royal Papworth Hospital building, opened in 2019, which has a state-of-the-art ventilation system to prevent transmission. ̽��ֱ��team recently published a study showing that this ventilation system was highly effective at reducing the amount of bacteria in the air.

Professor Julian Parkhill, joint senior author from the Department of Veterinary Medicine at the ̽��ֱ�� of Cambridge, added: “M. abscessus can be a very challenging infection to treat and can be very dangerous to people living with cystic fibrosis, but we hope insights from our research will help us reduce the risk of transmission, stop the bug evolving further, and potentially prevent the emergence of new pathogenic variants.”

̽��ֱ��team have used their research to develop insights into the evolution of M. tuberculosis – the pathogen that causes TB about 5,000 years ago. In a similar way to M. abscessus, M. tuberculosis likely started life as an environmental organism, acquired genes by horizontal transfer that made particular clones more virulent, and then evolved through multiple rounds of within-host evolution. While M. abscessus is currently stopped at this evolutionary point, M. tuberculosis evolved further to be able to jump directly from one person to another.

Dr Lucy Allen, Director of Research at the Cystic Fibrosis Trust, said: “This exciting research brings real hope of better ways to treat lung infections that are resistant to other drugs. Our co-funded Innovation Hub with the ̽��ֱ�� of Cambridge really shows the power of bringing together world-leading expertise to tackle a health priority identified by people with cystic fibrosis. We’re expecting to see further impressive results in the future coming from our joint partnership.”

̽��ֱ��study was funded by the Wellcome Trust, Cystic Fibrosis Trust, NIHR Cambridge Biomedical Research Centre and Fondation Botnar.

Reference
Bryant, JM et al. Stepwise pathogenic evolution of Mycobacterium abscessus. Science; 30 Apr 2021

Scientists have been able to track how a multi-drug resistant organism is able to evolve and spread widely among cystic fibrosis patients – showing that it can evolve rapidly within an individual during chronic infection.

We hope insights from our research will help us reduce the risk of transmission, stop the bug evolving further, and potentially prevent the emergence of new pathogenic variants

Julian Parkhill

Jon Sneddon

Patient with cystic fibrosis

̽��ֱ��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.

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Machine learning comes of age in cystic fibrosis

Anonymous — Fri, 23 Oct 2020 09:08:11 +0000

Accurately predicting how an individual’s chronic illness is going to progress is critical to delivering better-personalised, precision medicine. Only with such insight can a clinician and patient plan optimal treatment strategies for intervention and mitigation. Yet there is an enormous challenge in accurately predicting the clinical trajectories of people for chronic health conditions such as cystic fibrosis (CF), cancer, cardiovascular disease and Alzheimer’s disease.

“Prediction problems in healthcare are fiendishly complex,” said Professor Mihaela van der Schaar, Director of the Cambridge Centre for AI in Medicine (CCAIM). “Even machine learning approaches, which deal in complexity, struggle to deliver meaningful benefits to patients and clinicians, and to medical science more broadly. Off-the-shelf machine learning solutions, so useful in many areas, simply do not cut it in predictive medicine.”

Unlock this complexity, however, and enormous healthcare gains await. That is why several teams led by Professor van der Schaar and CCAIM Co-Director Andres Floto, Professor of Respiratory Biology at the ̽��ֱ�� of Cambridge and Research Director of the Cambridge Centre for Lung Infection at Royal Papworth Hospital, have developed a rapidly evolving suite of world-class machine learning (ML) approaches and tools that have successfully overcome many of the challenges.

In just two years, the researchers have developed technology that has moved from producing ML-based predictions of lung failure in CF patients using a snapshot of patient data – itself a remarkable improvement on the previous state of the art – to dynamic predictions of individual disease trajectories, predictions of competing health risks and comorbidities, ‘temporal clustering’ with past patients, and much more.

̽��ֱ��researchers are presenting three of their new ML technologies this week at the North American Cystic Fibrosis Conference 2020. In-depth details of the technologies and their potential implications are available on the CCAIM website.

̽��ֱ��tools developed by the Cambridge researchers represent astonishing progress in a very short time, and reveal the power of ML methods to tackle the remaining mysteries of common chronic illnesses and provide highly precise predictions of patient-specific health outcomes of unprecedented accuracy. What’s more, such techniques can be readily applied to other chronic diseases.

Applying new ML techniques in cystic fibrosis

“Cystic fibrosis is an excellent example of a hard-to-treat, chronic condition,” said Floto. “It is often unclear how the disease will progress in a given individual over time, and there are multiple, competing complications that need preventative or mitigating interventions.”

CF is a genetic condition that affects a number of organs, but primarily the lungs, where it leads to progressive respiratory failure and premature death. In 2019, the median age of the 114 people with CF who died in the UK was 31. Only about half of the people born in the UK with CF in 2019 are likely to live to the age of 50.

Cystic fibrosis is also a fertile ground to explore ML methods, in part because of the UK Cystic Fibrosis Registry, an extensive database that covers 99% of the UK’s CF population which is managed by the UK Cystic Fibrosis Trust. ̽��ֱ��Registry holds both static and time-series data for each CF patient, including demographic information, CFTR genotype, disease-related measures including infection data, comorbidities and complications, lung function, weight, intravenous antibiotics usage, medications, transplantations and deaths.

“Almost everyone with cystic fibrosis in the UK entrusts the Registry to hold their patient data, which is then used to ensure the best care for all people with the condition,” said Dr Janet Allen, Director of Strategic Innovation at the Cystic Fibrosis Trust. “What’s exciting is that the approaches developed by Professor van der Schaar take this to a completely new level, developing tools to harness the complexity of the CF data. Turning such data into medical understanding is a key priority for the future of personalised healthcare.”

Looking to the future

̽��ֱ��suite of new tools offers tremendous potential benefit to everyone in the CF ecosystem, from patients to clinicians and medical researchers. “Our medical ML technology has matured rapidly, and it is ready to be deployed,” said van der Schaar. “ ̽��ֱ��time has come to bring its clear benefits to the individuals who need it most – in this case, the people living with cystic fibrosis. This means collaborating further with clinicians and increasing our engagement with wider healthcare systems and with data guardians beyond the UK.”

Machine learning technologies have proven to be adept at predicting the clinical trajectories of people with long-term health conditions, and innovation will continue at pace. ̽��ֱ��patient-centred revolution in precision healthcare will enable and empower both clinicians and researchers to extract greater value from the growing availability of healthcare data.

̽��ֱ��challenge ahead is to realise the potential of these tools by making them available to clinicians and hospitals around the world, where they can help improve and save the lives of people living with chronic illness. This is one of the goals of the Cambridge Centre for AI in Medicine.

World-leading AI technology developed by the Cambridge Centre for AI in Medicine and their colleagues – some of which is being showcased this week at the North American Cystic Fibrosis Conference 2020 – offers a glimpse of the future of precision medicine, and unprecedented predictive power to clinicians caring for individuals with the life-limiting condition.

̽��ֱ��time has come to bring the clear benefits of machine learning to the individuals who need it most – in this case, the people living with cystic fibrosis

Mihaela van der Schaar

Hey Paul Studios

Blue and Brown Anatomical Lung Wall Decor

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Cambridge Heart and Lung Research Institute receives major funding boost

cjb250 — Wed, 10 Jul 2019 15:10:21 +0000

̽��ֱ��Institute will draw together the highest concentration of heart and lung researchers from academia, healthcare and industry in Europe. It has set an ambitious five-year target to demonstrate proof-of-concept for at least ten new drugs or diagnostic approaches in heart and lung diseases.

̽��ֱ��HLRI will be situated next to Royal Papworth Hospital, which was officially opened by HM the Queen on 9 July, and forms part of the Cambridge Biomedical Campus, the centrepiece of the largest biotech cluster outside the United States of America. It will be home to over 380 scientists and state-of-the-art laboratories in genomics, population sciences, research into cellular mechanisms of disease and translational science. It will also include a special ten bed facility where the first-in-patient studies of new treatments can be conducted.

“This is an incredibly exciting project bringing together world-renowned expertise in cardiovascular and respiratory science at Cambridge ̽��ֱ�� and clinical excellence at Royal Papworth Hospital,” says Professor Nick Morrell from the ̽��ֱ�� of Cambridge, Interim Director of the institute and a non-Executive Director of Royal Papworth Hospital.

“Heart and lung diseases affect many millions of people of people worldwide and the numbers are growing. Institutes such as ours, focussed on these big health challenges, are urgently needed. ̽��ֱ��discoveries made by our researchers will deliver major benefits to the public through improvements in public health, new approaches to diagnosing and treating disease, and new medicines.”

Professor John Wallwork, Chairman of Royal Papworth Hospital, said: “ ̽��ֱ��Heart and Lung Research Institute will mean new treatments will be created, tested and delivered to tackle the biggest causes of premature death in the world all on one site. This will be a huge step forward and demonstrates one of the reasons Royal Papworth Hospital moved to the Cambridge Biomedical Campus – to collaborate with the best researchers in the world to help to save lives. ̽��ֱ��importance of this building cannot be underestimated and I can’t wait to see how it will transform healthcare in the years to come.”

Image: Cambridge Heart and Lung Research Institute (artist's impression)

̽��ֱ��award is one of 11 announced from flagship capital investment scheme the UK Research Partnership Investment Fund, totalling over £670m of new investment into UK research and innovation. It complements £10 million of funding committed to the institute by the British Heart Foundation (BHF). Further funding will be provided by the ̽��ֱ�� and Royal Papworth Hospital, and the Wolfson Foundation.

̽��ֱ��BHF award, which contributes to the capital cost of the building, is one of the charity’s largest ever strategic award. ̽��ֱ��charity has also committed an additional £6m in funding for the BHF Cambridge Centre for Cardiovascular Research Excellence, which will be housed in the institute.

Professor Sir Nilesh Samani, Medical Director at the British Heart Foundation, said: “Through this funding we will help create a fantastic centre that will have a key role in driving forward our ambitious programme of heart and circulatory research. By bringing together world-leading scientists it will enable exciting opportunities for collaboration between researchers from different disciplines. And it will also accelerate the transformation of discoveries in the laboratory to treatments available at patients’ bedside.

“This grant is one of the largest the BHF has ever made and we have only been able to make this investment because of the incredible generosity of the public.”

̽��ֱ��Cystic Fibrosis Trust has also committed to raise up to £5 million to fund the Cystic Fibrosis Innovation Hub, which launched last year and will transfer to the new building once it has been completed. Both AstraZeneca and GlaxoSmithKline will also embed integrated research hubs in the Institute to maximise translational impact.

Work on the HLRI will begin almost immediately, with ground-breaking taking place in November 2019 and construction starting in early 2020.

Without further medical advances, an estimated one in four people in the UK will die from heart or circulatory disease, while one in five will die from lung disease. Combined, cardiovascular and respiratory diseases cost over £840 billion worldwide every year.

Chris Skidmore, Minister for Universities, Science, Research and Innovation, announced on 10 July 2019 a £30 million award to the ̽��ֱ�� of Cambridge to support the new Cambridge Heart and Lung Research Institute (HLRI).

This is an incredibly exciting project bringing together world-renowned expertise in cardiovascular and respiratory science at Cambridge ̽��ֱ�� and clinical excellence at the Royal Papworth Hospital

Nick Morrell

Cambridge Heart and Lung Research Institute (artist's impression)

Yes

New innovation hub aims to take a 'moon shot' at cystic fibrosis

cjb250 — Wed, 18 Apr 2018 14:01:05 +0000

John Winn’s office at Microsoft Research looks like that of any typical academic: on one wall is a whiteboard graffitied with impenetrable equations and mathematical scribblings, on the opposite wall books and files line shelves, and on his desk are photos of his family.

His desk, however, is somewhat different: it can rise or fall, depending on whether he wants to work standing or sitting – and underneath is a treadmill for walking and working at the same time. “There have been times when I’ve been deep in thought and almost fallen off it,” he jokes.

Winn has cystic fibrosis (CF) and keeping fit is an important part of managing his condition: the stronger his lung function, the better equipped he is to fight the potentially life-threatening infections that plague people living with the condition.

CF occurs when an individual inherits two copies of a single genetic variant, one from each parent. ̽��ֱ��disease causes a build-up of thick, sticky mucous in the lungs, intestines and organs, and those affected by the condition are particularly susceptible to lung infections leading to progressive inflammatory lung damage. Although life expectancy for people with CF has almost doubled in recent decades, it is still significantly below average.

Winn is a machine learning specialist and is using his expertise to fight the condition that affects his everyday life. Together with Professor Andres Floto from the Department of Medicine at Cambridge, he is turning data from the daily lives of people with cystic fibrosis into potentially life-saving information.

As part of this study, funded by the Cystic Fibrosis Trust and Royal Papworth Hospital, participants have been submitting data – everything from heart rate and lung function through to self-reported wellbeing – via an app that also monitors their activity levels. Machine learning then sifts through the data, looking for patterns and – it’s hoped – building a model that can predict when a patient’s health is about to deteriorate and advise them to seek medical help.

“ ̽��ֱ��overarching principle is about giving people control over their own health data and making it work for them,” says Winn. “There’s some informal feedback that just participating in the study and taking these readings has already improved health outcomes for some individuals: for example, it’s helped with adherence with taking their medications as they noticed that if they missed taking certain medicines, their readings got worse.”

̽��ֱ��project is just one strand of a major new Cystic Fibrosis Innovation Hub based on the Cambridge Biomedical Campus and run by Floto. ̽��ֱ��Hub is supported through a £5 million commitment from the Cystic Fibrosis Trust and matching funds from the ̽��ֱ�� of Cambridge. It will strengthen existing collaborations across the ̽��ֱ�� and with the Wellcome Trust Sanger Institute, as well as build new collaborative research networks with CF centres around the UK. ̽��ֱ��Trust’s Chief Executive, David Ramsden, said it will “provide in CF research across the country”.

Floto agrees with this sentiment: “We have an opportunity to uplift UK CF research in general by providing knowhow, training and reagents in a number of areas including genomics, bioinformatics, stem cells and clinical trials technology.”

A major part of the Hub’s activities will be around developing new drugs that target chronic inflammation in CF, in collaboration with the pharmaceutical company GSK as part of the GSK/Cambridge Strategic Partnership, as well as new antibiotic therapy for the main causes of lung infection in the condition.

Finding new drugs against these bacteria is becoming increasingly urgent – Floto and Professor Julian Parkhill at Sanger recently showed that Mycobacterium abscessus, the pathogen behind one of the most serious infections, is becoming increasingly multi-drug resistant and spreading globally. This is one reason why people with CF are advised not to meet each other.

“Clearly the techniques that we develop – and the drug-like molecules that come out of it – will have more general applicability to patients with other multi-drug resistant infections,” Floto says. This will be welcome news to England’s Chief Medical Officer, Professor Dame Sally Davies, who has warned of a future where “any one of us could go into hospital in 20 years for minor surgery and die because of an ordinary infection that can’t be treated by antibiotics.”

̽��ֱ��timing of all this is particularly good: Papworth Hospital, whose Adult Cystic Fibrosis Centre has gained a national and international reputation for its treatment of patients and its contribution to research, is due to move to the Biomedical Campus later in 2018. ̽��ֱ��CF wards will feature state-of-the-art air flow systems, designed with Floto’s work on the spread of multi-drug resistant CF pathogens in mind.

This close proximity between the patients and the researchers will help Floto test the new treatments he is pioneering. He is particularly excited about the potential for new cellular therapies he’s developing with Professor Ludovic Vallier at the Department of Surgery. Floto describes these as their “moon shot”. These would involve taking cells from a CF patient, re-programming them – correcting the genetic defect along the way – and then re-injecting them into patients. “This could provide a way to regenerate damaged lungs,” he says.

Floto knows his plans for the Hub are ambitious, but given that it’s almost 30 years since the gene that causes CF was discovered and there is still no cure for the disease, believes it’s time to take this shot at the moon.

Floto’s collaborators in the CF Innovation Hub include Chris Abell (Chemistry), Sir Tom Blundell (Biochemistry), Julian Parkhill and Ludovic Vallier.

Almost 30 years on from the discovery of the genetic defect that causes cystic fibrosis, treatment options are still limited and growing antibiotic resistance presents a grave threat. Now, a team of researchers from across Cambridge, in a major new centre supported by the Cystic Fibrosis Trust, hopes to turn fortunes around.

We have an opportunity to uplift UK cystic fibrosis research in general by providing knowhow, training and reagents in a number of areas including genomics, bioinformatics, stem cells and clinical trials technology

Andres Floto

Cambridge Biomedical Campus

A no-strings-attached scientific relationship

Professor Claire Bryant, like Floto, works on an inflammatory lung disease as part of the GSK/Cambridge Strategic Partnership. In her case, she’s looking at chronic obstructive pulmonary disease (COPD).

COPD is a condition caused by smoking, pollution and severe asthma. Bryant is looking in particular at how COPD makes the lungs ‘stickier’ to bacteria, increasing the risk of infections.

She holds two grants under the GSK/Cambridge Strategic Partnership, which aims to develop the next wave of ‘game-changing’ medicines by bringing academic and industrial expertise together to tackle often intractable disease. Based at Cambridge’s Department of Veterinary Medicine, Bryant currently has a three-day-a-week sabbatical at GSK’s headquarters in Stevenage. As such, it’s arguable whether anyone embodies the partnership more than she does.

̽��ֱ��three-year sabbatical provides Bryant with three postdocs, two PhD students and budget, with access to GSK resources, but with “no strings attached”. ̽��ֱ��only proviso is that if she works with a GSK reagent, they have first rights on what she does with this. Crucially, she says, it gives her “the space to think”.

Bryant is embedded in GSK’s Respiratory Drug Discovery Unit and attends its lab meeting every week. “I’ve met really smart, clever scientists at GSK, with different skills to those of us in academia,” she says. “I get to see all aspects of what happens at GSK, everything from how a target is identified to how drugs are developed to target it, through to taking these drugs to clinical trials. I see the whole spectrum.”

It is, though, a mutually beneficial programme, she stresses. Bryant brings her knowledge of innate immunity and her experience of multi-disciplinary collaborations, particularly in imaging. “It’s effectively like being a consultant,” she says. “I want them to get as much out of me as I do out of them.”

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

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Multi-drug resistant infection spreading globally among cystic fibrosis patients

cjb250 — Thu, 10 Nov 2016 19:00:00 +0000

̽��ֱ��study, led by the ̽��ֱ�� of Cambridge and the Wellcome Trust Sanger Institute, also suggests that conventional cleaning will not be sufficient to eliminate the pathogen, which can be transmitted through contaminated surfaces or in the air.

Mycobacterium abscessus, a species of multidrug resistant mycobacteria, has recently emerged as a significant global threat to individuals with cystic fibrosis and other lung diseases. It can cause a severe pneumonia leading to accelerated inflammatory damage to the lungs, and may prevent safe lung transplantation. It is also extremely difficult to treat – fewer than one in three cases is treated successfully.

It was previously thought that patients acquired the infection from the environment and that transmission between patients never occurred. ̽��ֱ��research team had previously studied one specialist CF centre in the UK and identified genetic and epidemiological evidence suggesting person-to-person transmission of M. abscessus but it was unclear whether this was a one off incident.

Now, by sequencing the whole genomes of over 1,000 isolates of mycobacteria from 517 individuals attending CF specialist centres in Europe, the US and Australia, researchers have demonstrated that the majority of CF patients have acquired transmissible forms of M. abscessus that have spread globally. Further analysis suggests that the infection may be transmitted within hospitals via contaminated surfaces and through airborne transmission. This presents a potentially serious challenge to infection control practices in hospitals.

Using a combination of cell-based and mouse models, the researchers showed that the recently-evolved mycobacteria were more virulent, likely to cause more serious disease in patients.

“This mycobacterium can cause very serious infections that are extremely challenging to treat, requiring combination treatment with multiple antibiotics for 18 months or longer,” says Professor Andres Floto from the Department of Medicine, ̽��ֱ�� of Cambridge, and the Cambridge Centre for Lung Infection at Papworth Hospital NHS Foundation Trust. “ ̽��ֱ��bug initially seems to have entered the patient population from the environment, but we think it has recently evolved to become capable of jumping from patient to patient, getting more virulent as it does so.”

Professor Julian Parkhill from the Wellcome Trust Sanger Institute at Hinxton, Cambridgeshire, adds: “Our research should provide a degree of hope: now that we know the extent of the problem and are beginning to understand how the infection spreads, we can start to respond. Our work has already helped inform infection control policies and provides the means to monitor the effectiveness of these.”

̽��ֱ��Adult Cystic Fibrosis Centre at Papworth Hospital, Cambridgeshire, has led the development and implementation of new infection control policies to reduce the risk of transmission, now adopted across the UK and elsewhere. This study has also influenced the design of a new CF unit, due to open within the New Papworth Hospital on the Cambridge Biomedical Campus in 2018, which will incorporate a state-of-the-art air handling system.

One question that the researchers will now aim to answer is how the pathogen manages to spread globally. Their current study has shown that not only can it spread between individuals within specialist centres, but it has also been able to spread from continent to continent. ̽��ֱ��mechanism for this is unclear, but the researchers speculate that healthy individuals may be unwittingly carrying the mycobacteria between countries.

̽��ֱ��sequencing data has also revealed potential new drug targets, and the team is now focused on working with other groups at the ̽��ֱ�� of Cambridge and Colorado State ̽��ֱ�� to develop these further.

Dr Janet Allen, Director of Strategic Innovation at the CF Trust, said: “This paper highlights the risks posed through transmission of multi-drug resistant organisms between people with cystic fibrosis. ̽��ֱ��team in Cambridge are a world authority in this area. This work demonstrates the global threat of this infection, the risks of cross-infection within and between CF centres, and the need for improved surveillance. This study exemplifies the enormous impact of CF Trust-funded Strategic Research Centres, which were designed to generate world-class research with the very highest impact. Without the support of the CF community, this landmark study would not have been possible.”

Around one in 2,500 children in the UK is born with cystic fibrosis, a hereditary condition that causes the lungs to become clogged up with thick, sticky mucus. ̽��ֱ��condition tends to decrease life expectancy among patients.

̽��ֱ��research was funded by the Wellcome Trust and the UK Cystic Fibrosis Trust.

Reference
Bryant, JM et al. Emergence and spread of a human transmissible multidrug-resistant nontuberculous mycobacterium. Science; 11 Nov 2016; DOI: 10.1126/science.aaf8156

A multi-drug resistant infection that can cause life-threatening illness in people with cystic fibrosis (CF) and can spread from patient to patient has spread globally and is becoming increasingly virulent, according to new research published today in the journal Science.

Our research should provide a degree of hope: now that we know the extent of the problem and are beginning to understand how the infection spreads, we can start to respond

Julian Parkhill

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'Mini bile ducts' help identify new drugs that could prevent the need for liver transplantation

cjb250 — Thu, 16 Jul 2015 10:44:30 +0000

For the first time, researchers from the Wellcome Trust-Medical Research Council Stem Cell Institute at the ̽��ֱ�� of Cambridge and the Wellcome Trust Sanger Institute in Cambridge, used stem cells to grow fully functional three-dimensional bile ducts in the lab. Bile ducts act as the liver’s waste disposal system, and malfunctioning bile ducts are behind a third of adult and 70 per cent of children’s liver transplantations.

̽��ֱ��researchers used their ‘miniature bile ducts’ to test new drugs for biliary disease, leading to the discovery that VX809 – an experimental compound originally designed to treat the effects of cystic fibrosis in the lungs – could be the first treatment to prevent the damage cystic fibrosis causes to the liver and bile duct.

Dr Fotios Sampaziotis, lead author and an MRC-Sparks clinical research fellow in hepatology at the Department of Surgery, said: “Treating liver complications caused by bile duct disorders constitutes a major challenge – with the only treatment option often being liver transplantation. Identifying a new experimental drug that could prevent patients with cystic fibrosis from undergoing a liver transplantation, a major and life changing operation, could have huge implications for our patients. But, this treatment will need to be tested in clinical trials before it can be recommended to patients.”

Until now there has been no way of generating large numbers of fully functional bile ducts that mimic disease in the lab, which has limited our understanding of biliary disorders and restricted the development of new drugs. Using their ‘bile duct replicas’ the researchers reproduced key features of two more bile duct diseases – polycystic liver disease and Alagille syndrome – and tested the effects of additional drugs, such as octreotide.

Professor Ludovic Vallier, Principal Investigator from the Wellcome Trust-Medical Research Council Stem Cell Institute and the Wellcome Trust Sanger Institute, said: “ ̽��ֱ��pharmaceutical applications of our system are particularly important as we don’t have many human samples of this type of tissue to work on. This system could provide a unique resource for identifying new treatments.”

Dr Nicholas Hannan, a senior author from the Wellcome Trust-Medical Research Council Stem Cell Institute, said: “ ̽��ֱ��bile duct cells we have generated represent an invaluable tool to understand not only how healthy bile ducts develop and function, but also how diseased bile ducts behave and how they may respond to treatment. This opens up the possibility of modelling complex liver diseases and will certainly progress our understanding of biliary disease in the future.”

To demonstrate that the cells they had grown were in fact forming bile ducts the researchers looked for characteristic markers and functions of the cells. They then compared these with samples from human donors and found that they were almost identical.

Dr Paul Colville-Nash, programme manager for stem cell, developmental biology and regenerative medicine at the MRC, said: “ ̽��ֱ��approach developed in this work will enable a vast range of work, from understanding how organs grow and develop to a greater understanding of disease and testing new drugs. This work could also one day open the way to researchers building new bile ducts that will replace damaged segments of the liver.”

̽��ֱ��study was funded by a joint MRC-Sparks clinical research training fellowship, the European Research Council and the European fp7 grant TissuGEN, the Cambridge ̽��ֱ�� Hospitals National Institute for Health Research Biomedical Research Centre, Addenbrooke’s Charitable Trust and the Wellcome Trust

Reference
Sampaziotis, F et al. Cholangiocytes derived from human induced pluripotent stem cells for disease modeling and drug validation. Nature Bioetch; 13 July 2015

Adapted from a press release from the Medical Research Council.

An experimental cystic fibrosis drug has been shown to prevent the disease’s damage to the liver, thanks to a world-first where scientists grew mini bile ducts in the lab.

Identifying a new experimental drug that could prevent patients with cystic fibrosis from undergoing a liver transplantation, a major and life changing operation, could have huge implications for our patients

Fotios Sampaziotis

Nature Biotechnology/ ̽��ֱ�� of Cambridge

‘Mini-bile ducts’ at day 25, stained with fluorescent dyes

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

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