Science for impact
VIB’s impact on society and the biotech ecosystem springs forth from the world leading science that is being done in all its centers. With this science as firm base, clinical applications, business collaborations, and spin-off creation are continuously developed in close contact with various units at VIB headquarters. The selection of paper here serves to illustrate the internationally recognized and cutting-edge work that VIB scientists from all VIB centers engage in. Their pioneering work is routinely published in leading scientific journals in several fields of the life sciences.
Immunology & inflammation
Dissolving protein crystals against asthma
Normally, proteins do not crystallize in the body, but there are some instances where this process does occur. Charcot-Leyden Crystals are made from the protein Galectin-10 and were discovered in the airways of asthmatics as early as 1853. However, the crystals have been largely ignored by scientists, and their actual link to disease remained unknown.
The groups of Bart Lambrecht and Savvas Savvides have now established that the crystals are highly abundant in airway mucus, stimulate the immune system and promote the inflammation and altered mucus production that is often seen in the airways of asthmatics. Together with the biotech company argenx, they developed antibodies that can dissolve these crystals to reduce key asthma features.
Persson et al., Science, 2019
Enzymes In 3D
Organisms across all kingdoms of life crucially rely on a molecule called acetyl-CoA that fuels essential biochemical processes in cells, such as the production of fatty acids and cholesterol. However, acetyl-CoA is not always easily available. To produce it, the enzyme ATP citrate lyase (ACLY) is needed.
The research team of Savvas Savvides and Kenneth Verstraete has unraveled the three-dimensional structure and molecular mechanism of ACLY. The reported findings could help targeting ACLY in cancer and metabolic diseases such as atherosclerosis. The structure of ACLY also unmasked a crucial evolutionary relationship that radically changes our understanding of the origins of cellular respiration. Verschueren et al., Nature, 2019
Tracking single cells
By combining single-cell profiling and computation trajectory inference tools, it is now possible to investigate the dynamics of individual cells at an unprecedented and purely data-driven detail.
The Yvan Saeys Lab has done a comprehensive benchmark of 45 different methods for trajectory inference. They highlight the complementarity of tools, provide guidelines for method users, and indicate open challenges in the field. All software tools are freely available from dynverse.org.
Saelens et al., Nature Biotechnology, 2019
Our brains do not only contain neurons, but also a variety of immune cells that play an important role for its functioning. Even a century after their discovery, one type of such immune cells – brain macrophages – continue to spark fascination.
Researchers from the Jo Van Ginderachter and Yvan Saeys labs combined single-cell transcriptomics with high-dimensional cytometry, fate-mapping and microscopy to reveal the origin and diversity of brain macrophages. This revealed the striking diversity of brain macrophages and found unexpected microglia. Remarkably, these ‘hidden’ microglia resembled those normally associated with disorders such as Alzheimer's disease.
Van Hove et al., Nature Neuroscience, 2019
Plant systems biology
Understanding radial growth
Besides obvious longitudinal growth, plants also enlarge in the radial sense. This thickening of plant stems and roots provides physical support to plants, provides us with wood and cork, and plays a major role in sequestering atmospheric carbon into plant biomass.
The lab of Bert De Rybel contributed to our understanding of plant radial growth by showing that DOF-type transcription factors control oriented divisions in specific procambium cells, suggesting that this seemingly homogenous tissue contains zones of high proliferation and quiescence. This will assist plant breeding for higher yield and atmospheric carbon capture through biomass increase. Miyashima et al., Nature, 2019 ,Smet et al., Current Biology, 2019
Curcumin for better biomass processing
To enhance the industrial processing of plant biomass into energy and valuable chemicals, plants can be engineered to contain alternative and easier-to-degrade lignins. Importantly, this intervention must not affect plant yield.
Researchers from the team of Wout Boerjan have now discovered that curcumin, a molecule natively produced by turmeric, can act as a building block for the lignin polymer, thereby significantly enhancing plant biomass processability. Oyarce et al., Nature Plants, 2019
A CRISPR knockout
Knocking out genes is a great way to learn what they do. After all, if you prevent a gene from doing its job and you notice changes, it’s very likely the gene has something to do with it. There is a caveat, though. If a scientist mutates a gene that is required for growth and/or reproduction, the mutant plants are often very sick or even die.
The teams of Thomas Jacobs, Moritz Nowack, and Tom Beeckman have now devised a CRISPR-based tissue-specific knockout system, CRISPR-TSKO. This system enables the generation of specific mutations in particular plant cell types, tissues, and organs. The efficiency of CRISPR-TSKO opens new avenues to discover and analyze gene functions during the life of plants while avoiding the effects of system-wide loss of gene function. Decaestecker et al., Plant Cell, 2019
Plant cells absorb many important substances through a process called endocytosis, which is essential for nutrient uptake, passing on cellular signals and plant–microbe interactions. However, the vital nature of endocytosis makes it challenging to be studied using methods from classical genetics.
The team of Jenny Russinova found a new chemical, ES9, that blocks endocytosis and discovered that this small molecule binds to clathrin, a protein that plays a major role in the formation of coated vesicles, small ‘organs’ in cells. Further in vitro binding studies and X-ray crystallography confirmed this interaction. Dejonghe et al., Nature Chemical Biology, 2019
Therapeutic antibodies are increasingly being used in the clinic for the treatment of various diseases. Yet, oral to gut targeting of antibodies remains a challenge due to their incapability to survive digestion and reach gastrointestinal tissues.
Now, the team of Nico Callewaert has developed a new antibody technology that combines the advantages of antibody-based therapies with the convenience of oral drug administration. Importantly, these antibodies are manufactured using yeast in a process as straight-forward as food-manufacturing. This may have uses in various areas, from fighting gut infections, treating inflammatory and metabolic disorders, to the development of microbiome altering food supplements. Virdi et al., Nature Biotechnology, 2019
A protein tag to study the immune system
To keep control of the expressed proteins, cells can attach a chemical ‘tag’ onto a protein to modify its activity. ISG15 is such a tag. However, the molecular function of ISG15 is elusive, since the identity of the modified proteins and their exact sites of modification are still unknown.
The team of Francis Impens took advantage of the technology developed to identify ubiquitin modification sites for the identification of ISG15 modification sites. With the newly developed method, scientists can now identify and study proteins tagged with ISG15, allowing them to unravel its many functions in fighting disease, potentially leading to novel antimicrobial drugs. Zhang et al., Nature Communications, 2019
Dismantling bacterial armor
What if we could fight pathogenic bacteria by stripping down their protective armor? Bacillus anthracis, the etiological agent of anthrax has a proteinaceous armor known as the S-layer.
An interdisciplinary study by the team of Han Remaut has shed light on the assembly and composition of this S-layer. Thanks to these insights, a new strategy to tear the armor apart using specific nanobodies was developed. When applied in vivo, these Nanobodies® worked as nanobiotics able to cure anthrax in mice. This study represents the first in vivo evidence that the disruption of bacterial S-layer integrity during infection has therapeutic potential. Fioravanti et al., Nature Mirobiology, 2019
Megabodies reveal GABAA structure
The Jan Steyaert lab has developed an innovative plug-and-play technology to graft functional Nanobodies® on several scaffolds with diverse properties to build Megabodies. Such Megabodies are game changing research tools in cryo-electron microscopy.
Here, the team applied the Megabody technology successfully, which lead to major new insights in the structure and functional mechanisms of human GABAA receptors. These receptors are the main mediators of rapid inhibitory neurotransmission in the vertebrate nervous system. They are among the most important human drug targets as they bind compounds with anticonvulsant, anti-anxiety, analgesic, sedative, and anaesthetic properties.
Masiulis et al., Nature, 2019
Metastasis through the lymphatic system
When breast cancer cells spread through the body, they do so mainly through the lymph system that normally removes excess fluid and waste products from our tissues. Growing tumors often put physical pressure on their environment, which makes these lymphatic vessels leaky and easier accessible for tumor cells. Now, scientists from the Massimiliano Mazzone lab identified a novel subset of immune cells, called Podoplanin-expressing macrophages (PoEMs), that change the tissues near a tumor in a way that promotes the spreading of cancer cells. Getting rid of these PoEMs in a mouse model strongly reduced the ability of breast cancer cells to move to other parts of the body. Bieniasz-Krzywiec P. et al., Cell Metabolism, 2019
Pyruvate as cancer food
Most cancer patients die due to metastasis formation. The local tumor environment is a crucial determinant of metastatic growth. The environment in which the cancer cells are embedded, the extracellular matrix (ECM), is a major component of this niche. Cancer cells remodel the ECM by hydroxylating collagen to promote their own metastatic growth.
The team of Sarah-Maria Fendt discovered that breast cancer cells rely on the nutrient pyruvate to remodel the lung metastatic niche. This study identifies the pyruvate metabolism as a new target for novel and selective strategies to inhibit metastasis formation without affecting healthy cells. Elia et al., Nature, 2019
Teaching normal cells to fight cancer
Current chemotherapies aim at killing rapidly proliferating cancer cells. However, such therapies are often only temporarily effective because cancer cells quickly evolve drug resistance. The Hippo signaling pathway has been implicated in tumor growth, sparking interest in the pathway as a potential therapeutic target.
In a study of liver cancer in genetically manipulated mice, the Georg Halder team discovered that the role of this pathway in tumorigenesis is more complex than previously appreciated. They found that whether tumor cells survive or are eliminated depends on competing signals produced by the tumor and surrounding tissue. Moya et al., Science, 2019
Towards a safer therapy for leukemia
T-ALL—short for T-cell acute lymphoblastic leukemia—is a form of cancer characterized by the presence of too many immature white blood cells. “T-ALL mainly affects children and is rapidly fatal if left untreated. Current chemotherapy is very effective but causes long-term side effects, so there is an urgent need for less toxic targeted therapies.
The teams of Jan Cools and Bart De Strooper found that the relative abundance of two different versions of one of the gamma-secretase complexes was strikingly different in leukemia cells versus healthy cells. This discovery led them to explore whether inhibiting only this specific version of the complex would prove to be a safer treatment option. They saw that targeting only one type of complex was both effective and safe in mouse models and in leukemia cells from T-ALL patients. Habets et al., Science Translational Medicine, 2019
Neuroscience & molecular neurology
Studying human microglia in mice brains
Microglia cells, brain cells that are responsible for brain ‘maintenance’, are thought to play an important role in the development of Alzheimer’s disease. But they are not easy to study. Culturing them a in petri dish neglects the complex environment in which they usually function, and model organism, such as mice, have microglia that are too different from human ones to draw robust conclusions.
Here, the Bart De Strooper team shows that embryonic stem cell-derived human microglia successfully engraft the mouse brain. Upon exposure to oligomeric Aβ, a wide range of Alzheimer’s disease risk genes are expressed that are not readily studied in current mouse models for the condition. This work provides a unique humanized animal model that will allow elucidating the role of genetic risk in the pathogenesis of Alzheimer’s disease. Mancuso et al., Nature Neuroscience, 2019
A new mechanism of neurodegeneration
Charcot-Marie-Tooth disease (CMT) is an inherited neurodegenerative condition that affects 1 in 2500 individuals. Currently, however, it is still lacking effective treatment options. Over 90 genes are implicated in the pathology so far and these are involved in a variety of processes. This complexity makes it a difficult condition to study and treat.
New research by the Albena Jordanova team has demonstrated that an important group of molecules known as aminoacyl-tRNA synthetases – which help in translating RNA into proteins – can interfere with the transcription of DNA into RNA. This interference was found to be at the core of CMT disease in both fly and cellular models. Bervoets et al., Nature Communication, 2019
A look at cellular diversity
Our genomes are controlled by combinations of regulatory molecules that “switch on” target genes in our DNA. These regulatory molecules bind to so-called enhancer and promoter regions in our chromosomes. Understanding when and how they are activated, can teach us a lot about the cellular diversity in our bodies.
The Stein Aerts lab developed cisTopic, a probabilistic framework that provides insight into the mechanisms underlying regulatory heterogeneity within cell populations. The results allow the optimization of cell clustering and enhancer categorization, the identification of cell subpopulations and enhancers that represent shared epigenomic programs. Bravo González-Blas et al., Nature Methods, 2019
Human neurons in mouse brains
The brain cortex, the outside layer of our brain often referred to as grey matter, is one of the most complex structures found in living organisms. But how neural circuits develop in the human brain has remained almost impossible to study at the neuronal level.
A collaboration between the labs of Pierre Vanderhaeghen and Vincent Bonin investigated human cortical neuron development, plasticity and function, using a mouse/human chimera model in which xenotransplanted human cortical pyramidal neurons integrate as single cells into the mouse cortex. Furthermore, these cells were active and exhibit human ‘tempo’ in their activity. Their findings provide new insights into human neuronal development, and open novel experimental avenues for the study of human neuronal function and diseases. Linaro et al., Neuron, 2019
Signal transmission in alzheimer
Alzheimer’s-affected brains are riddled with so-called amyloid plaques: protein aggregates consisting mainly of amyloid-β. Although the pathological role of the amyloid-β precursor protein (APP) in Alzheimer’s disease is well-studied, the physiological role of this protein has remained elusive.
The teams of Joris de Wit and Bart De Strooper have uncovered that the secreted part of the amyloid precursor protein modulates neuronal signal transmission through binding to a specific receptor, GABABR1a. Binding suppressed synaptic vesicle release and modulated synaptic transmission and plasticity in mice, hinting that modulating this receptor could potentially help treat Alzheimer’s or other brain diseases. Rice et al., Science, 2019
Information flow in the brain
We use information about the world around us to guide our behavior. To get from detection to action, visual information is passed from the retina in our eye to different downstream brain regions. The nervous system consists of many different cells that work together in circuits.
The team of Karl Farrow has unraveled how our brain processes visual information. They identified specific roles for distinct neuronal cell types in passing on information from the eye to downstream brain regions that guide behavior. The researchers deciphered a projection-specific logic where each output pathway from a brain area called the superior colliculus sampled a distinct and limited set of retinal inputs. Such knowledge is essential to understand how sensory information guides our actions and decisions. Reinhard et al., eLife, 2019
Replay for better memory
When we experience something important, we usually remember it better over time. This enhanced memory can be the result of stronger memory encoding during the experience, or because of memory consolidation that takes place after the experience. But how replay contributes to the consolidation of experiences in a familiar context is unknown.
Researchers from the team of Fabian Kloosterman have now demonstrated that large rewards can selectively enhance performance during familiar but demanding spatial memory tasks. Post-learning hippocampal replay thus selectively reinforces spatial memory of highly rewarded locations in a familiar context. These insights could open future opportunities for treatments that help to strengthen memories. Michon et al., Current Biology, 2019
Astrocytes help the brain process information
When we are aroused the hormone noradrenaline is secreted, which helps us to better remember emotional situations compared to neutral ones. Noradrenaline is released across the entire brain and stimulates astrocytes, which listen and respond to locally active neurons. But how do astrocytes integrate this brain-wide signal with the specific activity of local neuronal networks?
A collaboration between the teams of Vincent Bonin and Matthew Holt revealed that noradrenaline plays a key role in how astrocytes track distinct information during behavior. The researchers found that astrocytes can integrate information on arousal state and sensory experience. These results also show that astrocytes can integrate two kinds of information – sensory and behavioral information. Slezak et al., Current Biology, 2019
Medieval super yeasts
Despite being beautiful and intriguing creatures, interspecific hybrids are mostly sterile and thus an evolutionary dead end. Such interspecific hybridizations are rare and seem to be favored by the domestication process.
In a joint effort, the teams of Kevin Verstrepen and Steven Maere discovered that yeasts used for the production of traditional Belgian beers are hybrids between Saccharomyces cerevisiae and Saccharomyces kudriavzevii. The hybrid yeasts combined important characteristics of both parental species, with the fermentation capacity of normal beer yeasts and the stress tolerance and capacity to form special aromas of more feral ancient yeasts. Analyzing the genomes of these as-yet unknown beer yeasts revealed details of how interspecific hybridization can drive evolution. Gallone et al., Nature Ecology & Evolution, 2019
A gut feeling for mental health
The relationship between gut microbial metabolism and mental health is a controversial topic in microbiome research. The notion that microbial metabolites can interact with our brain - and thus behavior and feelings - is intriguing, but gut microbiome-brain communication has mostly been explored in animal models, with human research lagging behind.
Researchers from the lab of Jeroen Raes described a novel approach to assess the gut-brain potential encoded in metagenomic datasets. This allowed the assembly of the first neuroactivity catalogue of human gut microbes and the identification of groups of microorganisms that are linked to quality of life and depression. The results provide population-scale evidence for microbiome associations with mental health. Valles-Colomer et al., Nature Microbiology, 2019
Waking up sleeping bacteria
Bacterial populations harbor a small fraction of transiently antibiotic-tolerant cells, so-called persister cells. Upon exit from the persister state, they can recolonize the host leading to relapse of the infection. It is currently unknown how this exit from the persister state is regulated.
Research by the Jan Michiels group unraveled the molecular basis of the mechanisms of persister awakening. Persister cell development is promoted by forming pores in the bacterial cell membrane. This results into a rapid loss of energy, pushing the bacteria into a low energy state or deep sleep. Importantly, this pore formation is only possible when two HokB peptides are linked together. These findings may lead to the design of antipersistence therapies. Wilmaert et al., Molecular Cell, 2019
Gut microbes and bowel inflammation
Over the years, many research groups worldwide have attempted to describe microbiota alterations associated with diseases. Especially IBD is a hot topic in microbiome research. Inflammatory bowel disease (IBD) groups several conditions characterized by chronic inflammation of the intestinal tract, including ulcerative colitis and Crohn’s disease.
The team of Jeroen Raes used their newly developed quantitative microbiota profiling method and the Flemish Gut Flora Project catalogue to describe gut microbiome alterations in inflammatory bowel disease and primary sclerosing cholangitis. Patients had an increased prevalence of an altered microbial community type – Bacteroides2 – surprisingly also previously linked to depression. Vieira-Silva et al., Nature Microbiology, 2019