3. The art of science across scales: from spins to cells

Borja Mateos (Molecular Biophysics Laboratory)

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The term 'scientist' was first coined in 1834 by William Whewell and his friends in Cambridge. In analogy to the term 'artist', the new term aimed to replace previous designations that described the job of teaching and conducting research in scientific disciplines. In fact, it remains valid to this day that great science involves a great art. The ability to reflect curiosity and creativity in one's work is of utmost importance in our profession and has significant implications for various aspects of society. The scientific method provides the framework to channel curiosity into well-defined questions and employ creativity in the necessary methodology. To address fundamental questions, it is typically necessary to characterize our system of study at various temporal and spatial scales, ranging from microseconds to years and from Angstroms to meters. Accomplishing this requires the integration of multiple disciplines, both in vitro and in vivo, as well as the expertise of numerous scientists.

 
Biophysics encompasses a wide range of techniques aimed at addressing fundamental questions in biomedicine, drawing upon physics, chemistry, and biology. In this course, students will learn how to employ their questions and curiosity to formulate hypotheses and design experiments. Specifically, they will gain an understanding of how a diverse set of in vitro experiments can contribute to unraveling the molecular mechanisms of diseases. This will involve the combination of atomic-resolution techniques, such as NMR spectroscopy with microscopy, and various analytical assays. As an illustrative example, the course will explore the significant role played by intrinsically disordered proteins in regulating cellular fate and potentially triggering pathogenic processes.

 

2. Mirror, Mirror on the Wall… Who Is the Most Helpful Insect of Them All? – Getting to Know Tumorigenesis Through the Fly 

Kaustuv Ghosh & Berta Muñoz (Development and Growth Control Laboratory)

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The fruit fly Drosophila melanogaster has been widely used as a model organism for   more than one hundred years to address biological questions in various fields. This organism has emerged as a potent tool for genetic manipulation, offering innumerable possibilities to analyse the detailed interaction between cells and tissues.

One     question     could     be     raised:     how     can     a     tiny     organism like D. melanogaster be used to understand the pathways of a disease as complex as cancer? The answer is quite simple. Many biological mechanisms are well conserved across evolution, including those related to pathological conditions. This conservation allows scientists to translate the knowledge acquired from less complex organisms to more complex ones. For instance, 75% of the genes related to human diseases and 68% of the genes related to human cancer have a counterpart in the fly. We are more similar to the fly than what we may think!

In this course, students will learn how to study the complex process of tumorigenesis using this model organism, both with a local and systemic approach. We will focus mainly   on carcinomas, the most common type of tumour diagnosed in humans.
Carcinomas are derived from epithelial tissue, such as the skin, and they can become invasive or metastatic by spreading beyond the primary tissue layer and surrounding tissues or organs. In aggressive cancer cells, this transition is mediated by the activation of the EMT (Epithelial to Mesenchymal Transition) program, which causes the cells to undergo morphogenetic alterations that increase invasive capacity.

In this course, students will be introduced to the first steps in fly genetics. We will cross flies, identify genetic markers and balancer chromosomes, and apply other genetic tools that we use in the lab every day in order to generate tumorigenic flies and study them. Students will also learn about the anatomy of the fly in adult and larvae stages and use advanced microscopy to see several genetic markers in the tumoral tissues. Finally, students will perform in vivo dissections and their respective immunohistochemistry

 

3. 1. 1. Unravelling Hematopoietic Stem Cells

Indranil Singh (Quantitative Stem Cells Dynamics)

 

Hematopoiesis depends on the preservation of a specific cell type called hematopoietic stem cells (HSCs). These long-lasting HSCs occupy the highest position in the hierarchy of hematopoietic cells and come with both self-renewal and pluripotent differentiation capacities. These HSCs differentiate into a full spectrum of mature blood cells through intermediate progenitor stages. While their long-term self-renewal potential helps in maintaining a source of primitive HSCs throughout one lifespan. At the same time, their ability to differentiate helps one to fight infection and disease. The balance between HSC self-renewal and differentiation is central to homeostasis and is regulated by the complex interplay of extrinsic and intrinsic regulatory networks.

As they age, HSCs gradually lose their differentiation potential. In our current effort, we are trying to understand the molecular mechanisms that contribute to HSC aging. We argue that most of the causes that underlie HSC aging result from cell-intrinsic pathways. Because many hematological pathologies are strongly age-associated, hence there has been an increasing interest in strategies to intervene in aspects of the functional stem cell expansion for transplantation or targeting the stem cell aging process could be of significant clinical relevance.

This course provides hands-on experience to learn the basic techniques to culture hematopoietic stem cells and they will be trained to induce ex-vivo differentiation. They will also have the opportunity to perform in vitro assays that will help you to recognize the cell types based on cell surface markers. During this workshop, you will be introduced to FACS (Flow activated cell sorting) concepts of suspension and adherent cell culture, media formation, and genomic DNA extractions.

 

4. Using the Protein-Eating Machine to Treat Cancer

Jake Antony Ward (Targeted Protein Degradation and Drug Discovery Laboratory)

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The control of the concentration, structure and location of proteins is important for the health and fitness of our cells. When proteins are damaged or are no longer needed, they are broken down within the cell in a process known as degradation. One of the main cellular systems involved in degrading unwanted or damaged proteins is called the proteasome. The proteasome is a large structure made up of many enzymes, such as proteases, which recognise and break down these proteins. For a damaged or unwanted protein to be recognised and broken down by the proteasome, a specific label, known as ubiquitin, is usually added to the protein. Certain enzymes known as ubiquitin ligases are involved in this tagging process.

In recent years, drugs have been developed that use this proteasome system in our cells to degrade a certain protein. This is an exciting new strategy, as it can allow us to the remove a given protein from a tumorogenic cell. This approach is known as Targeted Protein Degradation (TPD). This technology works by using a drug that brings the ubiquitin ligase and the target protein for degradation closer together. The protein is thus labelled with the ubiquitin-tag and is recognised by the proteasome and destroyed.  

In this course, students will focus on a type of cancer known as Gastrointestinal Stromal Tumour (GIST). This cancer typically develops in the muscle cells of the gut. When mutated, the KIT protein is the molecule responsible for the formation and growth of this type of cancer. We are interested in designing drugs using the TPD strategy to remove KIT from GIST cancers. This line of research is exciting as it may lead to new treatments for GIST.  Students will gain hands on experience of the key techniques of gel electrophoresis and Western blotting to monitor the degradation of KIT in human cancer cells.

5. Machine learning to fight drug resistance

Gema Rojas (Structural Bioinformatics and Network Biology Laboratory)

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Drug resistance, which occurs when previously vulnerable cells become unresponsive to specific drugs, poses a significant  public health concern worldwide. Antimicrobial resistance (AMR) exemplifies this issue, with estimates indicating that the annual death toll resulting from AMR could skyrocket from 700,000 to 10 million people by 2050. Similarly, drug resistance impacts the efficacy of cancer treatment, as patients may develop resistance following a relapse. The primary driver of drug resistance involves mutations in the DNA sequence of proteins associated with the drug's mode of action.

To comprehensively study this phenomenon, a crucial step involves analysing DNA sequencing data and establishing connections with protein structure and function to enhance our understanding of resistance mechanisms and devise strategies to overcome them. Machine learning has emerged as a valuable tool in predicting drug resistance by leveraging sequencing data.

In this course, students will have the opportunity to explore public databases and extract relevant biological information concerning drug resistance. They will work hands-on with sequencing data to understand the significance of mutations and observe how alterations in the sequence impact the shape and function of proteins. Finally, they will build a small machine learning model to predict drug resistance on the basis of sequence data.