What? In this project, the gene editing CRISPR/Cas9 system will be used to disable lung cancer cells in a laboratory setting. The gene editing will be directed by a synthetic guide RNA sequence that will be optimised by comparing the effect of many such compounds with subtle modifications. When several highly active RNAs have been developed, they will be conjugated to a carrier system that will ensure delivery to cancer cell. The carrier system is based on cell penetrating peptides that will be optimised to target the cancer cells. The final conjugates are expected to deliver more than 50% of the RNA in a 24 period and suppress the cancer cells at least three times more effective than current guide RNA. Why? Gene editing holds huge promise as treatment for human diseases such as cancer. In order to realize this potential, several challenges first have to be solved. Ensuring that the developed drugs reach the cancer cells and the correct targets within the cells is one of those challenges. This is challenging because the bimolecular drugs are relatively large and unstable compared to traditional small molecule drugs that require less or no assistance in reaching their site of action. This project can provide new tools to direct bimolecular drugs for gene edition and is therefore an important part of the further development of gene editing technology as a whole. How? The experimental plan for this project will begin by optimizing the guide RNA that directs the gene editing. The RNA will be chemically modified to ensure stability and increase function. Sequencing will be used to show that the targeted cancer genes are successfully disabled and to what extent off-target genes are damaged. Next, the carrier peptides will be optimized to transport the guide RNA into lung cancer cells. Fluorophores will be used to track the compounds and visualize how they enter the cell. Once suitable pairs of guide RNAs and peptides have been identified, they will be connected in such a way that the RNA can be released inside the cell and exert the cancer disruptive function.

What? The marine soundscape has dramatically changed since the Industrial Revolution. With increasing traffic, ship noise has become the most ubiquitous and pervasive source of anthropogenic noise in the ocean. Sound travels fast and with little attenuation in the aquatic environment, and consequently, whales and dolphins have evolved to rely on sound for communication, navigation, and foraging. However, baleen whales in particular hear best and produce sound at the same frequencies where cargo ships make the most noise, likely making them the most sensitive species to vessel noise disturbance. Why? Baleen whales engulf massive amounts of food and have an important role in the marine ecosystem, not only as consumers, but also as prey to other predators, and as reservoirs of nutrients in the deep. Baleen whales are therefore key to maintain healthy marine environments, and hence, a decrease in their populations can have detrimental impacts. For over 50 years, numerous studies have documented short-term adverse effects on baleen whales exposed to vessel noise, including changes in behaviour, and decreases and/or cessations in foraging. However, there is still a lack of data on i) the specific noise levels that trigger changes in behaviour, and ii) how these noise-induced behavioural changes impact the fitness of the exposed individuals. How? Through VESSEL, I propose to fill these important knowledge gaps by applying an innovative combination of state-of-the-art tagging technology and noise analysis to, for the first time in baleen whales, i) quantify received noise levels on the animal, and ii) estimate a dose-response relationship between vessel noise levels and the energy budget of the exposed individuals. The outcomes of VESSEL will be crucial to link disturbance parameters to individual fitness and population dynamics. Importantly, VESSEL will be of direct relevance to the management of underwater noise levels in EU marine waters by providing evident-based estimates of critical noise thresholds for the fitness of baleen whales.

The rhythmic contraction of our heart is controlled by electrical impulses that travels throughout the cardiac muscle. The signal is generated by the sinus node, which can be thought of as the natural pacemaker of our heart. Heart failure is a global health problem and studies have reported that concomitant sinus node dysfunction is an important predictor of mortality, yet its molecular underpinnings are poorly understood. In our recent work we have identified a pharmacological target that enable us to mitigate sinus node dysfunction in an animal model of heart failure. In the present project we aim to improve our understanding of the detailed molecular build-up of the sinus node, and to investigate the translational perspective of our discovery.What? Why? How?

What? Drug counterfeits are fake drugs intentionally produced with a commercial outcome. Drug counterfeits are a worldwide problem that yearly causes thousands of deaths due to substitution of the active drug compound(s), limited drug production control, and reduced or no pharmaceutical effect of the counterfeited drugs. Up to 10% of all drugs are counterfeit and this number increases every year. Why? Non-visual drug counterfeits (e.g. changes in chemical formula or composition) are particularly challenging to identify due to the lack of chemical methods. I hypothesize that the components and the production method of a drug leave a specific chemical fingerprint. Genuine drugs and counterfeits will have different chemical fingerprints. How? In this project, I will combine knowledge and methods from geology to establish a new pharmaceutical methodology to identify and understand drug counterfeits through isotopic ratio and trace elemental analysis. My work anticipates generating new and important chemical approaches to spot non-visual drug counterfeits. Thereby, I aim to improve drug safety and ultimately reduce the number of yearly deaths related to drug counterfeits.

What? The main purpose is to explore how organizing in extreme contexts (e.g., close to war zones, natural disasters, and events such as the current pandemic) is taking place, and how those that attempt to create (social) change, adapt and cope with the work themselves Why? State of the art literature has called for "robust actions" (Ferraro et al., 2015), spurring increasing advocacy for research on large-scale problems confronting humanity in extreme contexts (e.g., Haellgren, Rouleau and de Rond, 2018). My research attempts to shed light on some important issues, however neglected aspects of organizing in extreme contexts and grand societal challenges, studying in the context of the global pandemic, (1) how work practices were disrupted and changed, interrupting traditional knowledge flows necessitating actors to (radically) change, (2) how those that attempt to alleviate the suffering of patients cope with the work themselves. How? During this research stay at Stanford University, I will focus on the organizational features of extreme contexts by (1) engaging in data collection and (2) fostering existing and new collaborations. My research attempts to shed light on some important issues, however neglected aspects of organizing in extreme contexts and grand societal challenges, studying in the context of the global pandemic, (1) how work practices were disrupted and changed, interrupting traditional knowledge flows necessitating actors to radically change, (2) how those that attempt to alleviate the suffering of patients cope with the work themselves.