By Heather Hobbs
BRINGING YOU THE LATEST NEWS & EVENTS FROM THE SCIENCE INDUSTRY Human Lung Cell Atlas reveals Cell Type Diversity
a first integrated reference atlas of the human lung, which includes data from more than a hundred healthy people and reveals how the cells from individuals vary with age, sex, and smoking history. The sheer numbers of cells and individuals involved now gives us the power to see rare cell types and identify new cell states that have not previously been described.”
Dr Malte Lücken, Group Leader at the Institute of Computational Biology and the Institute of Lung Health & Immunity at Helmholtz Munich added: “A comprehensive organ atlas requires many datasets to capture the diversity between both cells and individuals, but combining different datasets is a huge challenge. We developed a benchmarking pipeline to find the optimal method to integrate all datasets into the atlas, using artificial intelligence, and combined knowledge and data from almost 40 previous lung studies.”
Recent single-cell technologies have given researchers an insight into which genes are active in each cell in a particular organ. However this method is both time- consuming and expensive and generally, only include a limited amount of people in each study. Now researchers from the Wellcome Sanger Institute, Helmholtz Munich, University Medical Center Groningen and collaborators have created an integrated single-cell atlas of the human lung by combining 49 different published and newly generated datasets. Using AI-based techniques, this comprehensive cell map provided insights into cellular differences between healthy people, as well as rare cell types.
Professor Fabian Theis, Head of the Computational Health Center, Director of the Institute of Computational Biology at Helmholtz Munich and Professor at the Technical University of Munich (TUM), explained the project: “We have created
“Obtaining a refined lung atlas helps us understand the cellular landscape of our respiratory system and will enable us to better understand how diseases, such as COVID-19 or asthma, occur and how we might prevent them,” said Dr Kerstin Meyer, Principal Staff Scientist in the Cellular Genetics team at the Wellcome Sanger Institute. “What makes our study so important is the vast amount of data analysed, with information from over 400 individuals, and over 40 datasets, many of which have been developed at the Wellcome Sanger Institute.”
The team discovered that different lung diseases shared common immune cell states, including the finding that a subset of macrophages (a type of immune cell) shared similar gene activity in lung fibrosis, cancer and COVID-19. The shared states indicate that these cells could play a similar role in scar formation in the lung in all three diseases, and provide pointers for potential therapeutic targets.
Professor Martijn Nawijn, a senior author on the paper and Professor at the University Medical Center Groningen,
the Netherlands, said: “This is the first effort to compare healthy and diseased lungs in one study in an integrated way. Our study not only supports the presence of lung fibrosis in COVID-19, it allows us to identify and define a shared cell state between lung fibrosis, COVID-19 and lung cancer patients. Finding these shared disease-associated cells is really exciting, and reveals a totally different way of looking at lung diseases, opening possibilities for novel treatment targets and developing treatment response biomarkers. Our findings also suggest that therapies working for one disease may help alleviate others.”
The Lung Atlas Integration project was a large collaborative effort with nearly 100 partners from more than 60 departments involved internationally, including key researchers from the University Medical Center Groningen and Northwestern University. The team is part of the Human Cell Atlas (HCA) Lung Biological Network, which has its roots in the Chan Zuckerberg Initiative Seed Networks for the HCA, and the European Union funded lung network DiscovAIR. At the start of the pandemic in 2020, the single-cell lung communities came together rapidly, forming the HCA Lung Biological Network to help understand COVID-19, which then catalysed the effort to integrate all the data.
The atlas has been made fully publicly available and it is expected to serve as a central resource for doctors and scientists that want to better understand lung biology in health and disease and develop further studies.
An integrated cell atlas of the lung in health and disease. Lisa Sikkema et al. (2023). Nature Medicine. DOI: 10.1038/ s41591-023-02327-2
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Early Stage Apoptosis Mechanisms Revealed
by perforating the cell mitochondrial membrane to form pores that trigger cell death.
This can be offset by Bcl-2, which embedded within the mitochondrial membrane, acts to prevent untimely cell death by capturing and sequestering Bax proteins. In cancerous cells however, the survival protein Bcl-2 is overproduced, leading to uninhibited cell proliferation.
To gain further insights, the team used the neutron reflectometry capability of the advanced ISIS Surf and Offspec instruments, enabling them to study in real time how BAX interacts with lipids in the mitochondrial membrane.
Credit: STFC ISIS Neutron and Muon Source
Researchers led by Dr Luke Clifton at the Science and Technology Facilities Council (STFC) ISIS Neutron and Muon Source (ISIS) in Oxfordshire and including partners from the University of Umea and European Spallation Source in Sweden, have been able to characterise the molecular mechanism of the early stages of programmed cell death (apoptosis) a process which plays a crucial role in the prevention of cancer.
Apoptosis is regulated in normal cells by two proteins with opposing roles; the Bax protein clears old or diseased cells
They discovered that when Bax creates pores in the membrane, it extracts lipids to form clusters on the mitochondrial surface via a two-stage process:
• Fast adsorption of Bax on the mitochondrial membrane surface.
• Simultaneous formation of membrane-destroying pores and Bax-lipid clusters.
This is the first time that scientists have found direct evidence of the involvement of mitochondrial lipids during membrane perturbing in cell-death initiated by Bax.
The finding builds on previous studies by the team on the molecular mechanism of membrane-bound Bcl-2 to inform a full understanding of the early stages of apoptosis.
Dr Clifton, STFC ISIS Scientist and lead author, explained: “This work has relevance not only to our understanding of fundamental mammalian cell processes but to our understanding of cancer cells. In order to develop effective cancer treatments, we need to characterise every step of the process by which cancerous cells spread so that we can identify opportunities to intervene in this process.
“This research has provided another piece of the jigsaw and has moved us one step closer to tackling cancer before it takes hold. It also really shows the capabilities of neutron reflectometry in structural studies on membrane biochemistry.
Professor Gerhard Gröbner, University of Umeå and co-lead author said: “The unique findings here will not only have a significant impact in the field of apoptosis research but will also open gateways for exploring Bax and its relatives as interesting targets in cancer therapy such as by tuning up their cell-killing potential.”
Continued research is already planned at ISIS to probe this mechanism further in the hope of revealing insights into potential targets for pharmaceuticals.
Published in Science Advances More information online:
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