Publication highlights

This paper describes a multiscale computer model that simulates the dynamics of individual molecules within the complex architecture of a living cell. Biological molecules show dynamic changes in structure and position over a very wide range of time scales (from nanoseconds to many tens of seconds) and move over physical dimensions that range from nanometres to tens of micrometres. These dynamic ranges can be difficult to simulate and model. The paper presents a multiscale modelling environment that helps to bridge the gap between the very rich experimental data sets and some basic underlying physical-chemical understandings of molecular interactions.

Researchers at the Francis Crick Institute, The Hospital for Sick Children (SickKids) and Johns Hopkins University have found that mitochondria depend on a newly discovered recycling mechanism in order to clear away damaged sections and continue functioning. Using high resolution microscopy, the team identified that a mitochondrion’s damaged crista can squeeze through its outer membrane. A lysosome then engulfs the crista and breaks it down. The scientists named this process VDIM (‘vesicles derived from the inner mitochondrial membrane’) formation.

Wear-and-tear means the lining of the gut is continually refurbished. Gut stem cells self-renew or differentiate (change state) into transit amplifying (TA) cells, which in turn either cycle or differentiate into mature gut epithelial cells. TA cells have an additional superpower: they can de-differentiate to replenish the stem cell pool after damage. Vivian Li's lab have found that when ARID3A is knocked out in mice, there are more mature cells and fewer TA cells, as the balance between the two states is disturbed. Further, the ability to repair irradiation-induced damage to the stem cell pool is hampered as damaged stem cells cannot be replaced efficiently from the depleted TA cell pool. These findings reveal the hitherto unrecognised role of ARID3A in coordinating the gut proliferation–differentiation ratio important for both steady-state and injury-induced gut regeneration.

Our cells need acidic compartments for digestion and recycling of nutrients. Acid is pumped in by a complex assembly of proteins called the V-ATPase. But what happens when our cells get damaged? The acid leaks out and the cell has to respond. Researchers at the Crick discovered how the V-ATPase proton pump itself sounds the alarm: one protein in the complex recruits a crucial part of the self-eating (autophagy) machinery. They think this is especially important during infection since some bacteria target this pathway, and many viruses like influenza trigger it.

How can cellular signalling quickly change the set of expressed genes (transcriptome) to drive fast biological changes? The RNA Networks Laboratory used deep learning to discover dynamic RNA binding patterns, or ‘mRNA hubs’, at the ends of mRNAs that control a developmental cell fate transition. These mRNA hubs undergo major changes in ribonucleoprotein assembly upon ERK signalling. This signalling leads to phosphorylation of the protein LIN28A, which then converges within mRNA hubs with another protein, PABP, to induce selective decay of mRNAs which are no longer needed to maintain pluripotent cell fate. This is required for progression of early development.

A collaboration between the Antimicrobial Defence Laboratory, led by Venizelos Papayannopoulos, and Joanna Porter, Professor of Respiratory Medicine at UCL and Consultant at UCLH, has found that a drug commonly used to treat cystic fibrosis improved outcomes for patients with severe COVID-19 pneumonia. This drug could be used to treat other respiratory infections in the future. The study found that the drug dornase alfa reduced hyper-inflammation in COVID-19 pneumonia patients, which occurs when the body’s immune system reacts too strongly and can lead to tissue damage and death. The next step will be to conduct larger clinical trials to ensure dornase alfa is safe and effective for treating severe COVID-19 pneumonia. There is also potential for the drug to be trialled for other respiratory infections and conditions.

Researchers at the Crick have used cryo-EM to unveil the structure of an assembled retrovirus, called Prototype Foamy Virus (PFV), revealing the structure and function of the virus' surface proteins and internal capsid. The surface protein which is used in entering host cells was found to be similar to proteins on the surface of parainfluenza viruses and coronaviruses, an unexpected relationship. PFV is a promising vector system for gene therapy and cancer treatment.

Researchers at the Francis Crick Institute have mapped all the possible outcomes of changes to a tumour-suppressing gene called VHL. They used a new method called saturation genome editing to track the function of over 2,000 different VHL variants in human cells over time, finding that most variants did not impact the survival of the cells, suggesting that people with these variants may not have a significantly higher risk. Other variants were shown to be faulty and caused the cells to die, suggesting people with these variants could be monitored for cancer risk. This could also identify people with VHL mutations who would benefit from certain drugs like belzutifan.

The microbiome has been recognised as an essential element in the body's protection against infectious agents. Microorganisms enter the body through different routes, including the oral one, making it an important niche for potential pathogens. An imbalance in the composition of the oropharyngeal microbiome can lead to increase risks of respiratory tract infections, which still represent a major public health problem worldwide, particularly in developing countries. Characterising the microbiome of this ecological niche in developing countries is essential for identifying biomarkers of infections. This manuscript presents the results of the first study on the link between the oropharyngeal microbiome and symptomatic upper respiratory tract infections in children in Côte d'Ivoire. It provides a description of the microbiota as well as an understanding of potential microbial markers of infection for pathogens such as Streptococcus pneumonia, Haemophilus influenza and Sars-Cov2. The results of this study add to the knowledge on the microbiome in diverse and understudied settings.

Properly folding all the proteins manufactured in a cell is crucial for all biological functions, but despite billions of years of evolution in which to perfect the process, proteins often misfold. Molecular chaperones assist the folding process during protein synthesis, but how chaperones work together to recognise nascent protein chains and enable correct folding is not well understood. The Balchin lab at the Crick, in collaboration with the Chemical Biology, Structural Biology and Proteomics teams, has now used advanced mass spectrometry techniques to explore how complex, multidomain proteins fold during synthesis. Their study shows how different classes of chaperone interact with and protect proteins at different stages of folding, and sets the stage for further insights into how sequential, coordinated chaperone action during protein synthesis assists in maintaining healthy cells.

Cyclic peptides are an exciting new drug modality that can be used against disease targets that have been impossible to treat with traditional small molecule drugs. However, despite their promise, it can still be difficult to develop peptides for many important drug targets due to challenges with making the target protein for drug screening. To address this, researchers at the Crick have developed and applied a new method to discover cyclic peptides without the need for making the target by performing the screening process directly in the target’s native cellular environment. In the future this will allow cyclic peptide drug discovery against a wide range of previously undruggable targets.

A key step for the spread of cancer, called metastasis, involves the generation of a deeply altered tissue environment (termed niche), however, elucidating the underlying programs driving its origin is a significant challenge. In this study, researchers at the Crick dissected the early stages of breast cancer metastasis to the lung in mice. They found that the alveolar cells, which under normal conditions are the site of oxygen exchange, de-specialise and enter a state generally associated with repair upon an injury. This environment allows the tumour cells to thrive. The researchers propose the idea that by reverting the local specialisation of the tissue, metastatic cells can construct a new environment that benefits them.