Gravitation award for FLOW: "We will be able to steer the fates of proteins"

Interdisciplinary approach to make an impact

The Dutch government is investing more than 11 million euros in a major research project led by Utrecht University. The consortium of researchers involved in FLOW will, for the first time, comprehensively chart the supervision of specific proteins within the cell, from cradle to grave. Ultimately, leveraging this understanding, they aim to exert control over the fate of these proteins. Such insights could pave the way for novel therapeutic approaches targeting diseases like Parkinson's and cystic fibrosis.

The funding is part of the esteemed NWO Gravitation Programme, a government initiative that, for a decade already, has been dedicated to supporting top-tier research. Biennially, teams of researchers affiliated with Dutch universities can secure funding. Initially, research projects receive half of the allocated funds, with the remainder granted upon successful evaluation after five years. Thus, in the instance of FLOW, an additional 11 million euros could be awarded in five years' time. The principal investigators are Ineke Braakman (Utrecht University), Mireille Claessens (Twente University), Friedrich Förster (Utrecht University), Mark Hipp (UMC Groningen), Stefan Rüdiger (Utrecht University) and Alfred Vertegaal (Leiden UMC).

Het team dat meewerkt aan FLOW
The international FLOW team

Unreal

Professor Ineke Braakman had to wait a long time for the results, which meant that the project had already faded somewhat into the background. The surprise hence was all the more profound when she, as the project's leader, received the relieving phone call. "It felt completely surreal," she recalls, "but in the evening it slowly sank in.” It brings both joy and the realisation that lots of activities suddenly need to be set in motion. “The top priority now is to convene the consortium and embark on the tasks at hand."

Our aim is to make a substantial impact by examining the same two proteins across diverse scientific domains

Combining disciplines

For the very first time, researchers are set to construct a comprehensive overview of all the mechanisms contributing to the functionality of specific proteins within the cell. Their objective is to unravel precisely how the cell ensures accurate folding and maintenance of proteins, spanning from their creation through their functioning to eventual degradation. Additionally, they want to know how the cell disposes of a protein if it folds incorrectly.

Achieving this entails deciphering a network of helper proteins, commonly referred to as chaperones. Over the past fifty years, science has been studying this issue, albeit with a focus on various proteins and facets of the process. "Our aim is to make a substantial impact by examining the same two proteins across diverse scientific domains," Braakman elucidated. "In doing so, we aim to achieve a complete understanding of the entire system."

Protein diseases

Gaining a comprehensive understanding of the processes underlying protein function is crucial. This is because failures in these processes often lead to protein-related diseases. In Loss-of-Function (LoF) diseases, like metabolic disorders and cystic fibrosis, the malfunctioning arises from a specific protein's failure to adopt the correct structure. Conversely, Gain-of-Toxicity (GoT) diseases such as Alzheimer's and Parkinson's result from proteins improperly folding, forming toxic aggregates.

Within this research project, scientists are focusing on two proteins: CFTR, implicated in cystic fibrosis when dysfunctional, and alpha-synuclein, associated with Parkinson's disease when malfunctioning.

Novel therapies

In the second branch of the research, scientists aim to replicate the chaperone networks and processes responsible for protein care in a controlled laboratory setting. "The goal is ambitious”, Braakman remarked, "but as chemists often assert: true comprehension is only acquired when you can build it." This knowledge should eventually empower researchers to manipulate the system directly. "This way, we'll soon have the ability to influence the destiny of these proteins," Braakman added. Such capabilities will serve as the groundwork for novel therapies targeting protein-related ailments like Parkinson's and cystic fibrosis. Additionally, the results will make it easier to control a wide range of other disease-related proteins for medical and biotechnological purposes.

Gravitation award for ANION

The ANION project, of which Utrecht Professor Petra de Jongh of the Debye Institute for Nanomaterials Science is one of the applicants, also received a Gravitation award. In this multidisciplinary research program, chemists and physicists will lay the groundwork for new efficient electrochemical technologies that should lead to a drastic reduction in humanity's carbon footprint.

A large-scale energy transition requires efficient electrochemical processes for generating, converting and storing energy. Current electrochemical processes have major limitations and are not adequate for this purpose. There is currently insufficient knowledge of the processes taking place in electrochemical systems at the very smallest scale. This is what is needed to fundamentally improve them.

Gravitation award for iCNS

The Institute for Chemical Neuroscience (iCNS) is also a recipient of a Gravitation award. Utrecht Professor Maarten Kole is one the applicants. The aim of iCNS is to elucidate the molecular changes relating to psychiatric symptoms. Neurobiologists, chemists, psychiatrists, and data science experts will collaborate closely to achieve this. In contrast to traditional brain research, the researchers in iCNS will start with human brain material. The research should pave the way to improving the diagnosis and treatment of neuropsychiatric disorders such as depression, frontotemporal dementia and anxiety disorders.