IMOL STORYLINE FOR THE LAY AUDIENCE AND BEYOND
Human progress has given us longer, more fulfilling lives, but at the same time we are affected by more and more dangerous diseases. Lifestyle diseases are a modern-day plague. They are caused by imbalances in molecular homeostasis — the internal balance of the human body. The imbalances take the form of regeneration or degeneration at the molecular level, which is dangerous to human health.
What does a molecular imbalance cause?
Every year, 10 million people around the world are diagnosed with dementia – this means a new case every 4 minutes. These statistics will only get worse as, according to the World Health Organization, the number of cases of dementia may triple in the coming decades. This is mainly due to population growth and aging. In approx. 60% of cases dementia is the symptom of Alzheimer’s disease which affects 20 million people globally. This is only a fraction of all neurodegenerative diseases, with 60 million cases worldwide, and it is set to increase by another 20 million by 2030. (reference: World Health Organisation, . https://www.who.int/news-room/fact-sheets/detail/dementia )
An equally serious problem is cancer which is the cause of every sixth death. In 2020, the International Agency for Research on Cancer reported 19.3 million cancer cases, causing 10 million deaths worldwide. The COVID-19 pandemic had an additional impact on cancer care as a result of an increase in the number of patients who did not have access to medical facilities and effective healthcare. Cancer incidence projections clearly indicate that cancer may become the leading cause of death in Poland and around the world. (reference: The International Agency for Research on Cancer oraz WHO, https://www.iarc.who.int/news-events/latest-global-cancer-data-cancer-burden-rises-to-19-3-million-new-cases-and-10-0-million-cancer-deaths-in-2020/ )
Metabolic disorders also present a challenge in medicine. They are associated with the disruption of metabolic processes in the body. These may be rare inherited disorders (e.g. phenylketonuria, mitochondrial diseases), as well as those developed throughout the lifespan which can be managed to some extent, or prevented by changes in lifestyle (e.g. diabetes).
Metabolic diseases, such as diabetes, are civilization diseases which have emerged with the development of our civilization. About 30% of school-age children and 20% of adolescents are overweight or obese, which is a risk factor for type 2 diabetes and heart disease. Statistics demonstrate that every third adult in the world is overweight. (reference: National Institute of Diabetes and Digestive and Kidney Diseases, https://www.niddk.nih.gov/health-information/health-statistics/overweight-obesity )
More attention should also be paid to infections. Up to 3-4 infections per year for adults, and even 10 infections per year for children, aren’t a cause for concern. If they happen more often, this may be a sign that something is wrong in the body and the state of internal balance has been disturbed. Frequent infections may result from a regular lack of sleep, fatigue and long-term stress. The lack of a proper diet may also lead to homeostasis disorders, which means that the body does not have the energy to fight the illnesses, and is more susceptible to viruses and bacteria. Viruses disrupt molecular balance, and stress and fatigue exacerbate this condition. Recent years have shown that not only SARS-CoV-2 or the flu pose a significant threat, but also "forgotten diseases", such as polio and measles, which have been eradicated in many places worldwide due to national immunization programmes. (reference: American Family Physician, https://www.aafp.org/pubs/afp/issues/2001/0115/p257.html)
Infections with bunyaviruses are also becoming more and more prevalent. Bunyaviruses comprise approximately 350 viruses which are spread by infected mosquitoes, ticks and rodents. Bunyaviruses can cause hemorrhagic fever and viral encephalitis.
How can we fight civilization diseases?
Metabolic disorders, neurodegenerative diseases and cancer are all the result of disrupted molecular homeostasis, or the homeostasis of the body’s internal environment. In a properly functioning body homeostasis is maintained and everything works correctly. But when there are fluctuations from the norm, illnesses start to surface. It’s critical to detect the early phase of these diseases, the first symptoms, when doctors can begin treatment. This is why understanding the mechanisms that disrupt cellular homeostasis is so crucial.
A balance between regeneration and degeneration
An extreme example of disrupted homeostasis is degeneration which can lead to tissue necrosis, and is associated with e.g. aging. The lack of homeostasis in the brain, for example, is demonstrated in neurodegenerative diseases resulting in progressive neuronal damage (e.g. Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis). Regeneration is the process that helps to restore homeostasis. On the other hand, dysregulated, uncontrolled regeneration causes uncontrolled proliferation of cells and the development of tumors. The main causes of tumor development are genetic factors, exposure to carcinogens due to environmental pollution, and age-related physiological dysregulation. Aging population signifies an increase in the incidence of both cancer and neurodegenerative diseases.
Molecular biology has the answers
Research carried out at IMol on cell regulation at the molecular level is important for developing treatment for lifestyle diseases, such as age-related neurodegeneration, cancer and metabolic disorders. Gene expression analysis, including mRNA biology (Cieśla, Konarska, Mikulski, Gerlach), allows us to understand the management level in the cell and its impact on the physiological and biochemical development of the cell. The executive level, formation, activity and the dynamics of both the proteome (the entire set of the organism’s proteins) as well as higher order structures, such as membrane-bound organelles, is the next key element in understanding cell plasticity (Chacińska, Vascotto, De Franceschi, Szczepanowska, Proteomics Core Facility led by Serwa). Cell metabolism not only integrates the abovementioned mechanisms, but also describes biochemical changes, including the behavior of bioactive low molecular weight compounds (Azzi, Szczepanowska, Vascotto, Proteomics Core Facility led by Serwa). Signalling pathways and feedback loops are extremely significant in cell response and plasticity (Azzi, Marusiak, Vascotto). Research on viruses and their interactions with host cells is useful in understanding the viral mechanisms in taking over molecular processes in the cell (Gerlach, Chacińska). This knowledge is channeled by IMol scientists into solving biomedical problems that are important to society, by means of proposing new therapeutic strategies and treatments. The teams use various state-of-the-art tools in the fields of molecular, biophysical, theoretical and chemical research, focusing not only on describing the processes, but also on understanding their cause and effect relationships. Studies are carried out on various models — from the simplest, such as yeasts and nematodes, through human cell cultures, mice and patient-derived models.
What are the laboratories working on?
The areas in which the most promising research worldwide is conducted include bionanotechnology, synthetic biology, or the design of artificial biological systems modeled on natural ones, as well as systems biology which studies protein interaction and gene networks, and networks of metabolic pathways. Research in structural biology, cancer, neurodegenerative and age-related diseases, rare diseases, and the discovery of new drugs is crucial. Scientists aim to understand cellular processes that concern all the structural components of the cell — from nucleic acids and proteins to lipids and metabolites. This is how they unravel the complex networks that make the whole organism work. Disruptions in regeneration associated with stem cells and cancer, as well as infectious diseases and the potential molecular adaptation for personalized medicine present significant challenges.
IMol is an international research institute of the Polish Academy of Sciences which aims to find solutions to civilization diseases, genetic disorders and infectious diseases. The centre focuses on research in the effective diagnostics, treatment and prevention of such diseases. The Institute’s groups are made up of specialists from nearly 20 countries, including India, Italy, Germany, Turkey, Brazil, or Lebanon.
Research groups at IMol
What should we know about Dr. Abdelhalim Azzi’s Laboratory of Lipids and Chronobiology? Circadian clocks control 24-hour rhythms of several biological and physiological processes such as the sleep-wake cycle, body temperature, hormone release and metabolism. Indeed, metabolic processes in the liver follow a very precise circadian pattern to control and optimize energy use throughout the light/dark cycle. Metabolomic studies in mice and humans revealed that a large portion of metabolites changes in abundance every 24 hours, with daily variations in blood and saliva metabolites independent of sleep or feeding. Interestingly, the most rhythmic metabolites observed were lipids such as phosphatidylinositol (PtdIns). Phosphatidylinositol is a membrane phospholipid that can be phosphorylated at different positions of the inositol ring to generate phosphoinositides (PIs). Phosphoinositides kinases and phosphatases mediate the generation and interconversion of PIs. Despite their role in regulation of glucose and lipid metabolism, PI kinase and phosphatase activity with regards to their temporal circadian regulation of metabolism has not yet been investigated. The laboratory aims to dissect the role of these enzymes in regulation of circadian metabolic processes using in vitro and in vivo systems. The findings will improve knowledge about the role of phosphoinositides in circadian physiology.
Professor Agnieszka Chacińska’s Laboratory of Mitochondrial Biogenesis focuses on mitochondria which play a key role in metabolism and regulatory processes within a cell. Thus, the formation of mitochondria is essential for cellular function of every being in the eukaryotic kingdom, from unicellular organisms to mammals. Mitochondria comprise 1000-1500 cellular proteins which are synthesized outside of the mitochondria in the cytosol. The biogenesis of mitochondria relies on the efficient import, sorting, and maturation of proteins, all governed by conserved protein translocases and other complex biological machinery. The research conducted by the Laboratory of Mitochondrial Biogenesis explores novel and exciting links between protein transport mechanisms and mitochondrial protein homeostasis. The research group postulates the presence of unique mechanisms involved in protein biogenesis that involve crosstalk between the cytosol and mitochondrial compartments. The goal is to better understand the complex and dynamic processes involved in the formation of functional organelles, as well as the maintenance of cellular protein homeostasis and its failures, which result in pathology.
Homeostasis is the central theme of Dr. Maciej Cieśla’s Laboratory of Stem Cell RNA Metabolism. Homeostasis of all multicellular organisms is maintained by an elite set of cells with an unrestrained capacity to differentiate into all cell types — stem cells. Stem cells rely on a rapid rewiring of molecular pathways to maintain tissue integrity and re-populate pools of undifferentiated cells. Loss of these healthy characteristics is a cornerstone of aging and malignancy. Orchestrated regulation of post-transcriptional layers of gene expression, in particular mRNA translation and splicing, is an emerging determinant of cell fate choices. How these processes are coordinated to ensure fidelity of stem cell activation and allow for homeostatic balance is largely unknown. Activated stem cells embark on a complex programme that is frequently and notably uncoupled from the transcriptional regulation. How these extra-genomic states are acquired in dynamic stem cell transitions remains a key unanswered question. Similarly, the implications of the ‘non-transcriptional’ regulation of stem cell function were not comprehensively addressed so far. That is a fundamental biological conundrum of how post-transcriptional regulatory networks may be co-opted during the initial stages of stem cells activation. What drives these changes? And for which physiological and pathological processes are they important? The research group employs a pallet of stem cell systems to study rapid cellular fate switches during development. By a combination of genetic models, genome-wide sequencing approaches and mechanistic and structural technologies, the lab group studies the function of RNA metabolism during mammalian development. The group aims to understand the molecular basis of the post-transcriptional regulation of stem cell function. The objective of this research is to establish the molecular underpinnings of pathologies related to stem cell dysfunction, including infertility, congenital diseases, and cancer.
The Laboratory of Membrane Machines, led by Dr. Nicola De Franceschi, emphasizes that membranes are one of the fundamental biological polymers and they underpin a myriad of functions in the cell. Yet membranes are also intriguing with respect to their unique biophysical properties. This 5 nm-thick, fluid material is able to bridge scales across biology, holding an entire cell together while integrating the function of individual proteins that work at the nanometer scale. Membranes can expand and re-shape, undergo fusion and fission events, and even self-repair. And they do all of this with grace and elegance, enchanting us with their stunning beauty. The research group uses a bottom-up reconstitution approach to study biological nanomachines that function on membranes, such as membrane pores and membrane-deforming proteins. However, this is not limited to naturally occurring proteins: the group also uses other biopolymers such as nucleic acids to build bio-inspired machines that act in concert with membranes to create new functionalities. Finally, Dr. De Franceschi’s laboratory is interested in studying the still underappreciated role of membranes in the origin of life.
As Dr. Piotr Gerlach from the Laboratory of Structural Virology explains, RNA viruses are a diverse group of serious pathogens. Broadening structural insight into their molecular repertoire, and particularly virus-host intracellular interactions, is critical for a complete understanding of infection mechanisms. Host translation is one of the major sites of the virus-host battlefront. Being a center of cellular stress response pathways, it is often abused by viruses to produce viral proteins. Importantly, while the host translation gets switched off during infection, the viral one persists relying on the non-canonical translation strategies. Of particular interest is the fate of cytoplasmic RNA granules, since these compartments serve as a depository of host mRNA, stalled translation initiation complexes, and auxiliary factors that viruses can rely on during infection. Dr. Gerlach’s lab will combine structural biology expertise (cryo-EM, cryo-ET, and X-ray crystallography) with an in vivo platform – mammalian cell cultures transfected with minimal replicon systems, mimicking viral transcription and replication inside the infected cell. This platform will be used as a test tube for various assays, including whole genome CRISPR-Cas9 screens to identify novel host factors involved in viral infection, functional and localization studies, as well as structural analysis. Knowledge acquired on the way will open new research avenues that may ultimately lead to the design of innovative therapies and broad-spectrum antivirals.
Professor Magda Konarska’s Laboratory of RNA Biology uses the yeast S. cerevisiae spliceosome as a model of a complex molecular machine. The group aims to understand the details of its architecture and function. The goal of this research is to understand the complex set of substrate - spliceosome interactions during assembly and catalysis, affecting the positioning of reactive groups at the active site. The mechanistic studies in yeast will help the group understand the molecular interactions that influence splicing fidelity and alternative splicing in metazoan systems. The spliceosomal catalytic center undergoes dynamic changes during the catalytic phase of splicing. Changes of relative stabilities of competing conformations at the catalytic center affect splicing catalysis, altering splicing fidelity and thus affecting the selection of splice site sequences for catalysis. These findings have implications for alternative splicing, common to most Eukaryotes. Professor Konarska’s laboratory tests new models of snRNA: snRNA interactions at the catalytic center implicated in the function of the catalytic triplex and positioning of the branch site. The research group also studies spliceosomal factors involved in the substrate positioning for catalysis, in particular, those containing disordered protein domains penetrating the catalytic center. Another project investigates exon sequences that compensate for the defects of the intron 5’SS. Isolated yeast exon motifs are similar to metazoan exon enhancers. This striking sequence similarity suggests common underlying mechanisms of action. The hypothesis is that yeast exon motifs represent substrate binding sites recognized by the spliceosome. Professor Konarska’s group studies the molecular mechanisms underlying their function.
Dr. Anna Marusiak’s Laboratory of Molecular OncoSignalling is interested in cancer biology, cellular signalling during oncogenesis and the identification of novel targets for cancer therapies. Signal transduction plays an important role in cancer development, and protein kinases, being the master regulators of signalling pathways, represent key targets in cancer treatment. The research group wants to understand how aberrant signalling in cancer cells contributes to cancer development, metastasis or therapy resistance, and how that knowledge can be used to design novel anticancer treatments. In particular, the group focuses on investigating oncogenic signalling activated by MLK4 in breast cancer. MLK4 is a member of the Mixed-Lineage Kinase family of serine/threonine kinases that are activated by environmental stress, cytokines and growth factors, and play a role in a variety of cellular processes. The members of the MLK family have been involved in the regulation of a wide range of disorders including cancer, inflammation, metabolic and neurobiological disorders. The lab investigates MLK4 signalling in breast cancer where MLK4 is highly upregulated and contributes to malignant progression. One of the group’s projects is focused on understanding the role of MLK4 in the response to chemotherapy in breast cancer. Furthermore, Dr Marusiak’s laboratory aims to develop and validate the potency and efficacy of first-in-class MLK4-targeting compounds. The group is also interested in uncovering the importance of MLK4-dependent cross-talk signalling between components of the tumor microenvironment and breast cancer cells. The studies use human and mouse cancer cell lines, as well as syngeneic and xenograft tumor models in mice. Methods such as 3D cell cultures, flow cytometry, mass spectrometry and various phenotypic assays including invasion and migration assays are also used.
Dr. Karolina Szczepanowska's Laboratory of Metabolic Quality Control points out that metabolism is firmly defined by the mitochondria. They dictate the bioenergetic capacity of our cells and provide us with critical metabolites. The bulk of cellular energy is generated by the elaborative molecular machines embedded inside the mitochondrial membranes, jointly known as the OXPHOS system. The everyday stress impacts the composition and functionality of OXPHOS, leading to its dysfunction. Consequently, compromised OXPHOS fitness has been implicated in a broad spectrum of disorders, including cancer, diabetes, obesity, ischemia-reperfusion injury, neurodegeneration, or aging. What are the mechanisms that sculpture OXPHOS in response to challenges? Is there a way to repair it when injured by stress? The research group recently started to recognize that mitochondrial bioenergetics stay under the constant surveillance of dedicated proteostatic machinery. Yet the exact mechanisms and responsible players remain mostly elusive. The group’s research aims to dissect the mechanisms that mediate the quality control of OXPHOS exposed to disease-associated conditions and trace the molecular signals that steer its degradation. With the help of modern proteomics and advanced biochemical and molecular biology approaches, the research group can discover damage hot-spots in mammalian mitochondria and identify the factors responsible for their recognition and repair. The findings will help to understand how metabolic quality control contributes to the known cellular stress-responses. Furthermore, OXPHOS salvage can constitute an attractive target for novel therapies against a broad range of human diseases.
As Dr. Carlo Vascotto’s from the Laboratory of Mitochondrial Nucleic Acids explains, mitochondria are the primary endogenous source of reactive oxygen species (ROS): highly reactive molecules that can modify proteins, lipids, and nucleic acids. To ensure the stability of mitochondrial DNA and the functionality of transcription and translation processes, cells have evolved repair mechanisms and signaling pathways to detect and respond to ROS production. The lab studies the molecular mechanisms responsible for the repair of mtDNA lesions, the degradation processes of damaged mitochondrial mRNAs, and the characterization of mitochondrial-nucleus crosstalk in the regulation of mitochondrial functions.
Proteomics Core Facility led by Dr. Remigiusz Serwa: a closer look at proteins
IMol has its own proteomics laboratory where researchers conduct analyses that determine the level of protein expression in human cells or model organisms. The rate of protein synthesis or degradation is quantified, and its intracellular location is determined. Using proteomic methods to identify protein profiles, researchers analyse protein-protein or protein-small molecule interactions (e.g. a metabolite or a drug). All of the measurements are carried out using a Thermo Fisher Scientific mass spectrometer and an Orbitrap flow nanoliquid chromatography-tandem mass spectrometry set-up. A mass spectrometer analyses the substance’s elemental composition, and the Orbitrap determines the mass of ions. Measurements carried out with these instruments have a very high sensitivity, depth and repeatability of results. Both researchers at IMol and from outside the institute use the proteomics laboratory to support their research.
About us — highlights
We carry out research at the highest level, which is ensured by our international Scientific Board. The chair of the Board is Professor Phillip A. Sharp — a molecular biologist, geneticist, and Nobel Prize laureate in Physiology and Medicine (1993) for the discovery of split genes; there are 11 distinguished researchers serving in IMol Scientific Board in addition to IMol Directors.
We aim to work with researchers from all over the world who are recruited through an open recruitment system for advertised roles. Nearly 50% of IMol researchers are foreigners coming from 16 different countries.
Our research is focused on basic and applied molecular biology and biomedicine. We want to serve as an incubator for excellence, promoting creativity, productivity and innovation.
Research topics are determined through the selection of leaders whose ideas are evaluated during the recruitment process.
IMol has a proteomics core facility which focuses on protein expression analysis.
The institute is compact and dynamic, which contributes to our flexibility and organizational efficiency.
Our objective is to have an impact on people’s health. Our research creates the basis for new technologies.
We model our biomedical research on that carried out at the University Medical Center Göttingen, IMol strategic partner.
Over the past 2 years, we have established close partnerships with both research institutes and industry. Two of our partners are RealResearch and Molecure.