̽��ֱ�� of Cambridge - lung

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

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£16million gift to support Europe’s largest heart and lung research centre

cjb250 — Thu, 23 Mar 2023 14:00:31 +0000

̽��ֱ��Victor Phillip Dahdaleh Heart and Lung Research Institute (HLRI) is home to the largest concentration of scientists and clinicians in heart and lung medicine in Europe. It opened in July 2022 with the ambitious goal of identifying ten new potential treatments or diagnostic tests for heart and lung diseases within five years.

̽��ֱ��HLRI is located on Cambridge’s rapidly expanding Biomedical Campus, immediately adjacent to Royal Papworth Hospital. ̽��ֱ��institute brings together population health, laboratory and clinical scientists, with NHS clinicians and patients, with the aim of improving outcomes for people with cardiovascular and lung diseases such as heart attacks, pulmonary hypertension, lung cancers, cystic fibrosis and acute respiratory distress syndrome.

Dr Dahdaleh said: “Cambridge is one of the greatest Universities in the history of civilisation and, 800 years on, it is at the cutting edge of scientific progress. Over the years in which I have been supporting education and medical research around the world, I have realised the UK is a global leader in the prevention, identification and treatment of heart and lung diseases.

“I’m supporting this new Institute because, through collaboration with Royal Papworth Hospital and other leading institutions, it will enable a concentration of expertise that will make medical advances in these fields that are of international importance.”

Dr Dahdaleh has previously supported research at the ̽��ֱ�� of Cambridge looking into COVID-19 and national research on mesothelioma, a type of lung cancer linked to asbestos exposure. Cardiovascular and lung diseases kill more than 26 million people a year and have a major impact on the quality of life of many more. Alongside the immense human cost, the economic burden of these diseases – an estimated annual global cost of £840 billion – is already overwhelming and unsustainable. Yet declining air quality and increasing rates of obesity are set to compound the scale of the challenge faced worldwide.

Dr Anthony Freeling, Acting Vice-Chancellor of the ̽��ֱ�� of Cambridge, said: “We are truly grateful to Victor for his generous donation. There has never been a more pressing need to develop new approaches and treatments to help us tackle the heart and lung diseases that affect many millions of people worldwide. ̽��ֱ��Victor Phillip Dahdaleh Heart and Lung Research Institute is in a strong position to make a major difference to people’s lives.”

Professor John Wallwork, Chair of Royal Papworth Hospital NHS Foundation Trust, said: “When we moved our hospital to the Cambridge Biomedical Campus in 2019, one of our ambitions was to collaborate with partners to create a research and education institute on this scale. Victor’s kind donation will support all the teams working in HLRI to develop new treatments in cardiovascular and respiratory diseases, improving the lives of people in the UK and around the globe.”

̽��ֱ��HLRI includes state-of-the-art research facilities, space for collaboration between academia, healthcare providers and industry, conference and education facilities. It also includes a special 10-bed clinical research facility where the first-in-patient studies of new treatments are being conducted.

Professor Charlotte Summers, Interim Director of the HLRI, said: “We have set ourselves ambitious goals because of the urgent need to improve cardiovascular and lung health across the world. Victor’s generous gift will help us realise our ambitions. Collaboration is at the heart of our approach, with our researchers and clinicians working with patient, academic, charity and industry partners within the Cambridge Cluster, nationally and internationally.”

Dr Dahdaleh is also a significant supporter of the Duke of Edinburgh awards, York and McGill universities in his homeland of Canada, and the British Lung Foundation. Dr Dahdaleh and his wife Mona, via the Victor Dahdaleh Foundation, have a commitment to supporting scholarships for disadvantaged students pursuing higher education in addition to their extensive philanthropic support for research into cancer, lung and heart disease.

̽��ֱ��HLRI has already raised £30 million from the UK Research Partnership Investment Fund and £10 million from the British Heart Foundation, with additional funding from the Wolfson Foundation, Royal Papworth Hospital Charity and the ̽��ֱ�� of Cambridge. Additional support has been provided by the Cystic Fibrosis Trust for a Cystic Fibrosis Trust Innovation Hub within the institute.

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.

Identification of ‘violent’ processes that cause wheezing could lead to better diagnosis and treatment for lung disease

sc604 — Wed, 24 Feb 2021 00:01:31 +0000

̽��ֱ��researchers, from the ̽��ֱ�� of Cambridge, used modelling and high-speed video techniques to show what causes wheezing and how to predict it. Their results could be used as the basis of a cheaper and faster diagnostic for lung disease that requires just a stethoscope and a microphone.

Improved understanding of the physical mechanism responsible for generating wheezing sounds could provide a better causal link between symptoms and disease, and help improve diagnosis and treatment. ̽��ֱ��results are reported in the journal Royal Society Open Science.

At some point, most of us have experienced wheezing, a high-pitched whistling sound made while breathing. For most people, the phenomenon is temporary and usually the result a cold or mild allergic reaction. However, regular or chronic wheezing is often a symptom of more serious conditions, such as asthma, emphysema, chronic obstructive pulmonary disease (COPD) or certain cancers.

“Because wheezing makes it harder to breathe, it puts an enormous amount of pressure on the lungs,” said first author Dr Alastair Gregory from Cambridge’s Department of Engineering. “ ̽��ֱ��sounds associated with wheezing have been used to make diagnoses for centuries, but the physical mechanisms responsible for the onset of wheezing are poorly understood, and there is no model for predicting when wheezing will occur.”

Co-author Dr Anurag Agarwal, Head of the Acoustics lab in the Department of Engineering, said he first got the idea to study wheezing after a family vacation several years ago. “I started wheezing the first night we were there, which had never happened to me before,” he said. “And as an engineer who studies acoustics, my first thought was how cool it was that my body was making these noises. After a few days however, I was having real trouble breathing, which made the novelty wear off pretty quickly.”

Agarwal’s wheezing was likely caused by a dust mite allergy, which was easily treated with over-the-counter antihistamines. However, after speaking with a neighbour who is also a specialist in respiratory medicine, he learned that even though it is a common occurrence, the physical mechanisms that cause wheezing are somewhat mysterious.

“Since wheezing is associated with so many conditions, it is difficult to be sure of what is wrong with a patient just based on the wheeze, so we’re working on understanding how wheezing sounds are produced so that diagnoses can be more specific,” said Agarwal.

̽��ֱ��airways of the lung are a branching network of flexible tubes, called bronchioles, that gradually get shorter and narrower as they get deeper into the lung.

In order to mimic this setup in the lab, the researchers modified a piece of equipment called a Starling resistor, in which airflow is driven through thin elastic tubes of various lengths and thicknesses.

Co-author and computer vision specialist Professor Joan Lasenby developed a multi-camera stereoscopy technique to film the air being forced through the tubes at different degrees of tension, in order to observe the physical mechanisms that cause wheezing.

“It surprised us just how violent the mechanism of wheezing is,” said Gregory, who is also a Junior Research Fellow at Magdalene College. “We found that there are two conditions for wheezing to occur: the first is that the pressure on the tubes is such that one or more of the bronchioles nearly collapses, and the second is that air is forced though the collapsed airway with enough force to drive oscillations.”

Once these conditions are met, the oscillations grow and are sustained by a flutter mechanism in which waves travelling from front to back have the same frequency as the opening and closing of the tube. “A similar phenomenon has been seen in aircraft wings when they fail, or in bridges when they collapse,” said Agarwal. “When up and down vibrations are at the same frequency as clockwise and anticlockwise twisting vibrations, we get flutter that causes the structure to collapse. ̽��ֱ��same process is at work inside the respiratory system.”

Using these observations, the researchers developed a ‘tube law’ in order to predict when this potentially damaging oscillation might occur, depending on the tube’s material properties, geometry and the amount of tension.

“We then use this law to build a model that can predict the onset of wheezing and could even be the basis of a cheaper and faster diagnostic for lung disease,” said Gregory. “Instead of expensive and time-consuming methods such as x-rays or MRI, we wouldn’t need anything more than a microphone and a stethoscope.”

A diagnostic based on this method would work by using a microphone – early tests were done using the in-built microphone on a normal smartphone – to record the frequency of the wheezing sound and use this to identify which bronchiole is near collapse, and whether the airways are unusually stiff or flexible in order to target treatment. ̽��ֱ��researchers hope that by finding changes in material properties from wheezing, and locations that wheezes come from, the additional information will make it easier to distinguish between different conditions, although further work in this area is still needed.

Reference:.
A. L. Gregory, A. Agarwal and J. Lasenby. ‘An Experimental Investigation to Model Wheezing in Lungs.’ Royal Society Open Science (2021). DOI: 10.1098/rsos.201951

A team of engineers has identified the ‘violent’ physical processes at work inside the lungs which cause wheezing, a condition that affects up to a quarter of the world’s population.

Since wheezing is associated with so many conditions, it is difficult to be sure of what is wrong with a patient just based on the wheeze

Anurag Agarwal

Hey Paul Studios

Dimensional Lungs

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‘Mini-lungs’ reveal early stages of SARS-CoV-2 infection

cjb250 — Fri, 23 Oct 2020 08:29:27 +0000

To date, there have been more than 40 million cases of COVID-19 and almost 1.13 million deaths worldwide. ̽��ֱ��main target tissues of SARS-CoV-2, the virus that causes COVID-19, especially in patients that develop pneumonia, appear to be alveoli – tiny air sacs in the lungs that take up the oxygen we breathe and exchange it with carbon dioxide to exhale.

To better understand how SARS-CoV-2 infects the lungs and causes disease, a team of scientists from the UK and South Korea turned to organoids – ‘mini-organs’ grown in three dimensions to mimic the behaviour of tissue and organs.

̽��ֱ��team used tissue donated to tissue banks at the Royal Papworth Hospital NHS Foundation Trust and Addenbrooke’s Hospital, Cambridge ̽��ֱ�� NHS Foundations Trust, UK, and Seoul National ̽��ֱ�� Hospital to extract a type of lung cell known as human lung alveolar type 2 cells. By reprogramming these cells back to their earlier ‘stem cell’ stage, they were able to grow self-organising alveolar-like 3D structures that mimic the behaviour of key lung tissue.

Dr Joo-Hyeon Lee, co-senior author, and a Group Leader at the Wellcome-MRC Cambridge Stem Cell Institute, ̽��ֱ�� of Cambridge, said: “We still know surprisingly little about how SARS-CoV-2 infects the lungs and causes disease. Our approach has allowed us to grow 3D models of key lung tissue – in a sense, ‘mini-lungs’ – in the lab and study what happens when they become infected.”

̽��ֱ��team infected the organoids with a strain of SARS-CoV-2 taken from a patient in South Korea who was diagnosed with COVID-19 on 26 January 26 2020 after traveling to Wuhan, China. Using a combination of fluorescence imaging and single cell genetic analysis, they were able to study how the cells responded to the virus.

When the 3D models were exposed to SARS-CoV-2, the virus began to replicate rapidly, reaching full cellular infection just six hours after infection. Replication enables the virus to spread throughout the body, infecting other cells and tissue.

Around the same time, the cells began to produce interferons – proteins that act as warning signals to neighbouring cells, telling them to activate their antiviral defences. After 48 hours, the interferons triggered the innate immune response – its first line of defence – and the cells started fighting back against infection.

Sixty hours after infection, a subset of alveolar cells began to disintegrate, leading to cell death and damage to the lung tissue.

Although the researchers observed changes to the lung cells within three days of infection, clinical symptoms of COVID-19 rarely occur so quickly and can sometimes take more than ten days after exposure to appear. ̽��ֱ��team say there are several possible reasons for this. It may take several days from the virus first infiltrating the upper respiratory tract to it reaching the alveoli. It may also require a substantial proportion of alveolar cells to be infected or for further interactions with immune cells resulting in inflammation before a patient displays symptoms.

“Based on our model we can tackle many unanswered key questions, such as understanding genetic susceptibility to SARS-CoV-2, assessing relative infectivity of viral mutants, and revealing the damage processes of the virus in human alveolar cells,” said Dr Young Seok Ju, co-senior author, and an Associate Professor at Korea Advanced Institute of Science and Technology. “Most importantly, it provides the opportunity to develop and screen potential therapeutic agents against SARS-CoV-2 infection.”

“We hope to use our technique to grow these 3D models from cells of patients who are particularly vulnerable to infection, such as the elderly or people with diseased lungs, and find out what happens to their tissue,” added Dr Lee.

̽��ֱ��research was a collaboration involving scientists from the ̽��ֱ�� of Cambridge, UK, and the Korea Advanced Institute Science and Technology (KAIST), Korea National Institute of Health, Institute for Basic Science (IBS), Seoul National ̽��ֱ�� Hospital and GENOME INSIGHT Inc. in South Korea.

Reference
Jeonghwan Youk et al. Three-dimensional human alveolar stem cell culture models reveal infection response to SARS-CoV-2. Cell Stem Cell; 21 Oct 2020; DOI: 10.1016/j.stem.2020.10.004

Funding
̽��ֱ��research was supported by: the National Research Foundation of Korea; Research of Korea Centers for Disease Control and Prevention; Ministry of Science and ICT of Korea; Ministry of Health & Welfare, Republic of Korea; Seoul National ̽��ֱ�� College of Medicine Research Foundation; European Research Council; Wellcome; the Royal Society; Biotechnology and Biological Sciences Research; Suh Kyungbae Foundation; and the Human Frontier Science Program.

Image caption
Representative image of three-dimensional human lung alveolar organoid showing alveolar stem cell marker, HTII-280 (red) and SARS-CoV-2 entry protein, ACE2 (green). (Credit: Jeonghwan Youk, Taewoo Kim, and Seon Pyo Hong)

‘Mini-lungs’ grown from tissue donated to Cambridge hospitals have provided a team of scientists from South Korea and the UK with important insights into how COVID-19 damages the lungs. Writing in the journal Cell Stem Cell, the researchers detail the mechanisms underlying SARS-CoV-2 infection and the early innate immune response in the lungs.

We still know surprisingly little about how SARS-CoV-2 infects the lungs and causes disease. Our approach has allowed us to grow 3D models of key lung tissue – in a sense, ‘mini-lungs’ – in the lab and study what happens when they become infected

Joo-Hyeon Lee

Jeonghwan Youk, Taewoo Kim, and Seon Pyo Hong

Representative image of three-dimensional human lung alveolar organoid

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Punctured lung affects almost one in a hundred hospitalised COVID-19 patients

cjb250 — Thu, 10 Sep 2020 07:52:36 +0000

Like the inner tube of bicycle or car tyre, damage to the lungs can lead to a puncture. As air leaks out, it builds up in the cavity between the lung and chest wall, causing the lung to collapse. Known as a pneumothorax, this condition typically affects very tall young men or older patients with severe underlying lung disease.

During the pandemic, a team at the ̽��ֱ�� of Cambridge and Addenbrooke’s Hospital, Cambridge ̽��ֱ�� NHS Foundation Trust, observed several patients with COVID-19 who had developed punctured lungs, even though they did not fall into either of these two categories.

“We started to see patients affected by a punctured lung, even among those who were not put on a ventilator,” says Professor Stefan Marciniak from the Cambridge Institute for Medical Research. “To see if this was a real association, I put a call out to respiratory colleagues across the UK via Twitter. ̽��ֱ��response was dramatic – this was clearly something that others in the field were seeing.”

Professor Marciniak subsequently obtained the appropriate ethical approvals and exchanged anonymised clinic information about 71 patients from around the UK. This led to a study published today in the European Respiratory Journal.

Although the team are unable to provide an accurate estimate of the incidence of punctured lung in COVID-19, admissions data from the 16 hospitals participating in the study revealed an incidence of 0.91%.

“Doctors need to be alert to the possibility of a punctured lung in patients with COVID-19, even in people who would not be thought to be typical at-risk patients,” said Professor Marciniak, who is also a Fellow at St Catharine’s College, Cambridge. “Many of the cases we reported were found incidentally – that is, their doctor had not suspected a punctured lung and the diagnosis was made by chance.”

Just under two-thirds (63%) of patients with a punctured lung survived. Individuals younger than 70 years tended to survive well, but older age was associated with a poor outcome – a 71% survival rate among under 70s patients compared with 42% among older patients.

Patients with a punctured lung were three times more likely to be male than female, though this may be accounted for by the fact that large studies of patients with COVID-19 suggest that men are more commonly affected by severe forms the disease. However, the survival rate did not differ between the sexes.

Patients who had abnormally acidic blood, a condition known as acidosis that can result from poor lung function, also had poorer outcomes in COVID-19 pneumothorax.

Dr Anthony Martinelli, a respiratory doctor at Addenbrooke’s Hospital, said: “Although a punctured lung is a very serious condition, COVID-19 patients younger than 70 tend to respond very well to treatment. Older patients or those with abnormally acidic blood are at greater risk of death and may therefore need more specialist care.”

̽��ֱ��team say there may be several ways that COVID-19 leads to a punctured lung. These include the formation of cysts in the lungs, which has previously been observed in x-rays and CT scans.

Reference
Martinelli, A, et al. COVID-19 and Pneumothorax: A Multicentre Retrospective Case Series. European Respiratory Journal; 10 Sept 2020; DOI: 10.1183/13993003.02697-2020

As many as one in 100 patients admitted to hospital with COVID-19 develop a pneumothorax – a ‘punctured lung’ – according to a study led by Cambridge researchers.

Doctors need to be alert to the possibility of a punctured lung in patients with COVID-19, even in people who would not be thought to be typical at-risk patients

Stefan Marciniak

Carol VanHook

X is for X-ray

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Cambridge spin-out raises £7 million to develop treatments for lung disease

sc604 — Thu, 04 May 2017 15:57:10 +0000

̽��ֱ��company, Z Factor Limited, was founded by Professor Jim Huntington of the Cambridge Institute for Medical Research. ̽��ֱ��new funding has come from existing investor Medicxi, as well as Cambridge Innovation Capital and Cambridge Enterprise, the ̽��ֱ��’s commercialisation arm.

Z Factor is developing new treatments for Alpha-1-Antitrypsin Deficiency (AATD). AATD, which is a significant cause of liver and lung disease, results from a defect in the gene encoding Alpha-1-antitrypsin, a type of protein. Individuals with two defective copies of the gene, making up around 1 in 2000 of the Western population, typically develop emphysema starting in their 30s. They are also at an increased risk of developing liver diseases such as cirrhosis and cancer. Around 2% of people have one defective copy of this gene, and are at five-fold increased risk of developing Chronic Obstructive Pulmonary Disease (COPD) as they age.

̽��ֱ��most common mutation causing AATD is called the Z mutation, which disrupts the normal folding of the protein. Professor Huntington and his team obtained the crystallographic structure of this mutant form of Alpha-1-antitrypsin, which allowed for the first time the rational design of drugs that could correct folding and prevent the development of associated diseases. These small-molecule drugs act like molecular ‘chaperones’ for the defective protein, accelerating folding to the correct state.

Cambridge Enterprise helped in Z Factor’s formation in 2015, licensing key intellectual property to the company. ̽��ֱ��company has already identified dozens of molecules that can correct the folding defect caused by the Z mutation, and shown that some of these drug candidates can increase Alpha-1-antitrypsin levels in an in vivo model of AATD.

Z Factor is now working to select the best molecules for use as a drug in human trials. ̽��ֱ��company expects to reach the clinic with its lead candidate in 2019.

“We are delighted to work once again with Cambridge Enterprise to ensure this exciting basic science is rapidly and efficiently translated into new medicines for a surprisingly common and debilitating cause of liver and lung disease,” said David Grainger, Partner at Medicxi and Executive Chairman at Z Factor.

Following closely on the announcement of investments in ApcinteX and SuperX earlier this year, the Z Factor Series A brings the total raised during 2017 by companies founded by Professor Huntington, one of Cambridge’s most successful serial entrepreneurs, to almost £30 million. “Jim is a leading academic innovator and Z Factor is dedicated to developing a therapy that will address a serious unmet medical need,” said Christine Martin from Cambridge Enterprise, and a Director at Z Factor.

A ̽��ֱ�� of Cambridge spin-out company has raised £7 million in new funding, which will help in the development of treatments for liver and lung disease.

Jim Huntington

̽��ֱ��crystal structure of a trimer of Z alpha-1-antitrypsin revealed the C-terminal domain-swap mechanism of polymerisation and the structural defect caused by the E342K mutation.

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Scientists grow ‘mini-lungs’ to aid the study of cystic fibrosis

cjb250 — Fri, 20 Mar 2015 10:00:10 +0000

̽��ֱ��research is one of a number of studies that have used stem cells – the body’s master cells – to grow ‘organoids’, 3D clusters of cells that mimic the behaviour and function of specific organs within the body. Other recent examples have been ‘mini-brains’ to study Alzheimer’s disease and ‘mini-livers’ to model liver disease. Scientists use the technique to model how diseases occur and to screen for potential drugs; they are an alternative to the use of animals in research.

Cystic fibrosis is a monogenic condition – in other words, it is caused by a single genetic mutation in patients, though in some cases the mutation responsible may differ between patients. One of the main features of cystic fibrosis is the lungs become overwhelmed with thickened mucus causing difficulty breathing and increasing the incidence of respiratory infection. Although patients have a shorter than average lifespan, advances in treatment mean the outlook has improved significantly in recent years.

Researchers at the Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute used skin cells from patients with the most common form of cystic fibrosis caused by a mutation in the CFTR gene referred to as the delta-F508 mutation. Approximately three in four cystic fibrosis patients in the UK have this particular mutation. They then reprogrammed the skin cells to an induced pluripotent state, the state at which the cells can develop into any type of cell within the body.

Using these cells – known as induced pluripotent stem cells, or iPS cells – the researchers were able to recreate embryonic lung development in the lab by activating a process known as gastrulation, in which the cells form distinct layers including the endoderm and then the foregut, from which the lung ‘grows’, and then pushed these cells further to develop into distal airway tissue. ̽��ֱ��distal airway is the part of the lung responsible for gas exchange and is often implicated in disease, such as cystic fibrosis, some forms of lung cancer and emphysema.

̽��ֱ��results of the study are published in the journal Stem Cells and Development.

“In a sense, what we’ve created are ‘mini-lungs’,” explains Dr Nick Hannan, who led the study. “While they only represent the distal part of lung tissue, they are grown from human cells and so can be more reliable than using traditional animal models, such as mice. We can use them to learn more about key aspects of serious diseases – in our case, cystic fibrosis.”

̽��ֱ��genetic mutation delta-F508 causes the CFTR protein found in distal airway tissue to misfold and malfunction, meaning it is not appropriately expressed on the surface of the cell, where its purpose is to facilitate the movement of chloride in and out of the cells. This in turn reduces the movement of water to the inside of the lung; as a consequence, the mucus becomes particular thick and prone to bacterial infection, which over time leads to scarring – the ‘fibrosis’ in the disease’s name.

Using a fluorescent dye that is sensitive to the presence of chloride, the researchers were able to see whether the ‘mini-lungs’ were functioning correctly. If they were, they would allow passage of the chloride and hence changes in fluorescence; malfunctioning cells from cystic fibrosis patients would not allow such passage and the fluorescence would not change. This technique allowed the researchers to show that the ‘mini-lungs’ could be used in principle to test potential new drugs: when a small molecule currently the subject of clinical trials was added to the cystic fibrosis ‘mini lungs’, the fluorescence changed – a sign that the cells were now functioning when compared to the same cells not treated with the small molecule.

“We’re confident this process could be scaled up to enable us to screen tens of thousands of compounds and develop mini-lungs with other diseases such as lung cancer and idiopathic pulmonary fibrosis,” adds Dr Hannan. “This is far more practical, should provide more reliable data and is also more ethical than using large numbers of mice for such research.”

̽��ֱ��research was primarily funded by the European Research Council, the National Institute for Health Research Cambridge Biomedical Research Centre and the Evelyn Trust.

Inset image: Branching mini-lung. Credit: Nick Hannan, ̽��ֱ�� of Cambridge

Reference
Hannan, NR et al. Generation of Distal Airway Epithelium from Multipotent Human Foregut Stem Cells. Stem Cells and Development; 10 March 2015.

Scientists at the ̽��ֱ�� of Cambridge have successfully created ‘mini-lungs’ using stem cells derived from skin cells of patients with cystic fibrosis, and have shown that these can be used to test potential new drugs for this debilitating lung disease.

We can use these 'mini-lungs' to learn more about key aspects of serious diseases – in our case, cystic fibrosis

Nick Hannan

Hey Paul Studios

Blue and Brown Anatomical Lung Wall Decor

̽��ֱ��text in this work is licensed under a Creative Commons Licence. If you use this content on your site please link back to this page. For image rights, please see the credits associated with each individual image.

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̽��ֱ�� of Cambridge - lung

Scientists map how deadly bacteria evolved to become epidemic

£16million gift to support Europe’s largest heart and lung research centre

Read more: "There isn’t anything like it in the UK" - ̽��ֱ��new institute tackling some of the world's biggest killers

New Heart and Lung Research Institute opens

Identification of ‘violent’ processes that cause wheezing could lead to better diagnosis and treatment for lung disease

‘Mini-lungs’ reveal early stages of SARS-CoV-2 infection

Punctured lung affects almost one in a hundred hospitalised COVID-19 patients

Cambridge spin-out raises £7 million to develop treatments for lung disease

Scientists grow ‘mini-lungs’ to aid the study of cystic fibrosis