20th Sep 2022 - Secondment number one,
what a joy it has begun,
Budapest - what a great city,
Day or night, it always looks pretty.
Starting in the "ttk CompChem" team,
I soon setup my first parameter screen,
The objective; mapping allosteric GPCR binding,
considering chemistry, energetics, and membrane for the finding.
The project also took me virtually oversea,
starting new collaborations with Boston University.
Beyond - I got insights into QM/MM calculation,
which are important for covalent drug creation.
I signed up for a half-marathon,
and visited the lake Balaton.
Hungarian culture - opera, music, and dance are a treat,
and the Kakaóscsiga is now my favourite sweet.
21st Oct 2022 - Today is already my farewell,
one month went quickly, as I can tell.
Thank you for the beautiful time.
Being part of ALLODD is truly sublime.
Sziastok! from Budapest - Philosophizing about alternative careers and the meaningfulness of stays abroad - by ESR8 Nina-Louisa Efrém
Saturday, 6 am. Berlin’s central station is deserted (apart from a few Oktoberfest aficionados on their way to Munich) when I board the train that would take me to Budapest. One year into my PhD, time has come to depart for my first secondment. After having moved to Berlin, struggled to find an apartment and settled in a new lab, the script repeats itself. Luckily, one gets more and more used to relocations over time. Packing and saying farewells become a routine and – let’s be honest – the 2.5 months that I will spend in Budapest are a foreseeable period of time. Based on my first impressions, Budapest is a bustling city, enchanting with its mixture of crumbling Art Nouveau buildings, modern skyscrapers and panel buildings (Panelház) that reflect its moved history. It seems to be a wonderful place to live, and probably most important for me right now, to do science! I was provided a very warm welcome by my host lab, the Medicinal Chemistry Research Group at the Research Center for Natural Sciences and am now looking forward to getting my chemistry running here.
When I was younger, I assumed that one would need to become a world-renowned music star or at least a diplomate to travel the world for work and live in different countries. Since I cannot sing and my French is rudimentary, I ruled out these career options early on. The thought that a career in science would get me there had never occurred to me. University studies, conferences, secondments – the list of occasions for travel and stays abroad as a scientist (as a chemist in my case) is long. The basic principles of chemistry and physics apply across borders; the stereoselectivity of an SN2 reaction is the same in Canada and Cameroon, and dichloromethane will form the lower layer in a liquid-liquid extraction with water anywhere around the globe. The language of chemical formulas and mathematical expressions is beautifully universal. Consequently, work in science is predestined for international exchange. I like to think of science as a connective link between people and cultures but of course, it is a valid question why this cross-country mobility is important and how society in general benefits from it.
Taking a broader view on the meaningfulness of cross-border scientific exchange, I am convinced that it does not only accelerate scientific progress but likewise enhances multilateral collaboration to tackle the most pressing challenges of our time. It makes us aware that people anywhere around the globe are asking the same scientific questions and work hard to answer them. Collaboration in science can open hearts and doors to initiate partnerships in entirely different fields. The experience abroad gives us the possibility and at the same time responsibility to advocate for intercultural communication and tolerance towards different viewpoints, promoting diversity in our communities.
On a personal level, I realize that each stay abroad confronts me with different opinions and ways of living, making me more approachable and understanding. I have become more resilient and self-confident by overcoming unanticipated challenges. Over time, I have learned most problems can actually be solved, often with the help of others. Moving to different countries has sensitized me for things that are not going well in places where I have lived before and, on the other hand, made me appreciate even more those things that were working out smoothly. Of course, personal development is one thing, but I am also convinced that each stay abroad makes me improve on a scientific level. During the current secondment in Budapest, for instance, I am re-learning lab-techniques that I am rarely using in Berlin (simply because I was not aware of their applicability to certain problems) but that might save me a lot of time during my daily work. I am also learning how to perform experiments, types of chemical reactions and work procedures that are entirely new to me but standard in my Hungarian host lab. Taking this knowledge back to Berlin and sharing it with my colleagues there, will benefit all of us. Finally, working and discussing with my new colleagues, who have different backgrounds and experiences, makes me see certain things, e.g. steps of a procedure, from a different perspective. This deepens my understanding of the respective processes and makes me question routine operations. Of course, I am very much hoping that this process of knowledge sharing is not one-way but mutual to make this experience most rewarding for everyone involved.
Researcher’s Night is a vibrant festival of research, technology and innovation that takes place every year on the last Friday of September in many cities across the European continent. In Athens, it is hosted by one of the oldest and most prominent university foundations of the country, the National and Technical University of Athens, and it attracts numerous professionals from the educational field -teachers, professors, officials from the Ministry of Education- and, mostly, school and university students: children, teenagers and young adults aged 4 to 25.
Given its non-specialized audience that mainly consists of younger individuals, the central concept of this particular event is for researchers to share their work in a more creative and original manner in order to give visitors the opportunity to gain a more hands-on perspective of their scientific activities.
ALLODD successfully participated in this year's Research's Night in Athens, giving the opportunity to more than 250 interested individuals of all ages to get to know ALLODD Network, its objectives and actions. Being the first ITN to explore the concept of allostery in drug discovery, ALLODD aims to train the next generation of young scientists to exploit this concept and set the foundation for the emergence of the field. Cournia Lab was there in Researcher's Night in Athens, to communicate the science behind ALLODD to the general public. Such actions are of great importance and a major goal of the network, in order for more people to get familiar with the role of allostery in drug discovery.
You can find the material of the event by clicking in the button below.
GPCRs are a large family of transmembrane proteins representing a renowned target in drug discovery. Classical GPCR drugs are simply developed by targeting their orthosteric binding sites, yielding compounds that either activate or inactivate the protein. The main problem with this approach is that these sites are highly conserved among GPCR subfamilies, and this causes poor selectivity and possible side effects.
For this reason, in recent times the development of allosteric drugs, targeting GPCRs at sites that are different from the orthosteric binding sites, is getting increasingly relevant. The existence of such drugs has opened up the way for new therapeutic approaches and enriched the possible ways to modulate the functions of GPCRs1.
Many studies have underlined the importance of allosterism in the context of GPCR dimerization or higher-order oligomerization in the control of the physiological responses they modulate. Indeed, for many years, GPCRs have been studied as single functional units (i.e., monomers)1. However, recent evidence suggests that GPCRs can also work as higher-order oligomers constituted by equal (homo) or different (hetero) monomers.
In the case of oligomers, allosterism has a dual nature. On the one hand, a ligand alters the conformation of one monomer which then binds and modulates the configuration of the interacting receptor. On the other, the monomer itself can be considered as the allosteric modulator altering the conformation of the associated receptor, modulating its downstream efficacy and ligand affinity.
Therefore, GPCR oligomers have the potential to markedly expand the diversity and specificity of G protein-coupled receptor signaling, particularly in neural cells, where a few key receptors have been implicated in many neurological and psychiatric disorders, including addiction.
Several approaches have been designed to develop new drugs specifically targeting GPCR dimers. One possible way is to design a so-called bivalent ligand 2, a molecule composed of two pharmacophores that span the length of the dimer allowing it to dock at both ligand binding sites simultaneously. An example of this was reported by Gmeiner et al. in 20163 with a study focused on targeting the D2R- NTS1R heteromer via three different bivalent ligands. In addition to this, it is also possible to develop bitopic ligands that bind the allosteric site of a monomer and simultaneously modulate the functions of the other associated functional unit. This is the case for instance of the SB269652 allosteric modulator of the Dopamine D2 dimer4.
I began my PhD project at the Charité Institute shortly after moving to Berlin in the end of April of this year. Unfortunately, I had what I would qualify as a bit of a rough start. I had moved to another country before a few years ago already and thus thought I had an understanding of what to expect, but I underestimated how much of a challenge not being fluent in the language was going to be, especially with regard to finding a place to live. Additionally, I had to learn to perform long and complicated experiments unlike anything I had done previously. This, combined with a host of administrative issues, meant that the first few months of my PhD project were more difficult than anticipated.
And although luckily these issues did end up slowly but surely resolving themselves, the ALLODD workshop in Barcelona was still fortuitously timed. The change of pace, the interesting lectures and especially the opportunity to finally meeting my fellow ESRs from the program in person for the first time (as well as a number of the PIs) as I was unfortunately unable to attend the first workshop meeting in Vienna physically. The setup also facilitated networking, which I can otherwise find a bit daunting.
I was especially reminded of how interesting the field of GPCRs can be, both in academia and in the industry, and this comforted me in my decision to do a PhD centering on the study of the GPCR MC3R was indeed the right choice for me.
Furthermore, MC3R in particular seems to be on the rise in terms of the interest accorded to it by the scientific community. Indeed, it has been considered in the past to have a redundant role to its relative MC4R due to both having loss of function mutations connected to obesity. However, as it turns out the phenotype of these mutations for MC3R, unlike MC4R, includes an increase of the fat mass compared to lean mass as well as the mice models having trouble putting weight back after a period of restricted feeding. Moreover, several studies have also shown that MC3R variants in both mice and human patients result in the late onset of puberty and abnormal menstrual cycles, as well as a lowered expression of several genes in the circadian rhythm. Despite these observations of how MC3R mutants affect organisms’ phenotype, information regarding the intracellular trafficking of MC3R is unfortunately lacking due to commercially available MC3R antibodies being non-specific in their binding.
This makes the study of MC3R, specifically of its structure and its ligand binding affinity, particularly fascinating as it could very well elucidate some of the mystery that still surround this protein’s function, and I hope I will be able to take steps towards doing so in the coming months. I look forward to continuing improving my skills and pursuing my career both at the Charité Institute and within the ALLODD program.