The momentous research endeavor RESOLUTE has just achieved an incredible landmark. It deeply advances our knowledge on this topic of how chemical transport pathways work inside of human cells. Over the last ten years, 120 scientists from 13 institutions in three rivers and eight countries have collaborated. Their joint research has led to the first comprehensive protein-protein interaction maps, aka interactomes, for nearly 400 solute carriers (SLCs) transporters. The CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences takes the pioneering Austrian project. In doing so, it has shed new light onto transporter-encoding genes, a large part of which remains enigmatic.
The human genome includes hundreds of transporter-encoding genes, but a large fraction have mysterious functions. Among these, the SLC superfamily is highly notable as the largest and most diverse transporter group, filling essential and complex roles in many physiological and pathological processes. This massive research endeavor centers on de-coupling key proteins. These proteins have been found to be of extreme value when it comes to cancer treatment, metabolic diseases, and neurological diseases.
The Foundations of RESOLUTE
The RESOLUTE project began with a clear objective to systematically analyze the function of SLC transporters in human cells. To prioritize transporter imports, researchers took a brute force approach, effectively knocking out or overexpressing hundreds of SLC genes in human cell lines. This unique experimental design enabled them to identify distinct metabolic and gene expression signatures for 71 previously uncharacterized transporters.
The collaborative spirit of the project came together through a shared five years of intense, experimental data collection. In order to elucidate synthetic lethal interactions and functional redundancies among the transporters, researchers performed over 35,000 double-knockout experiments. These discoveries have shed light on new possible therapeutic targets, especially within mitochondrial SLCs.
“Coordinating the research efforts of such a large group of scientists was a formidable challenge, especially during COVID. We had to develop all sorts of creative strategies to keep partners focused and motivated—but it worked wonderfully. The success relies heavily on efficiently combining expertise across fields.” – Tabea Wiedmer, Project Manager
Insights and Resources Generated
The RESOLUTE knowledge base on how the project flipped the script on conventional wisdom. Its power lies in its ability to provide a detailed blueprint of chemical transport pathways in human cells. The comparative database annotates the majority of solute carriers with functionally informative residues. It provides a robust set of tools to the entire global research community.
Following the methodology above, the project has produced large datasets. These will propel future studies to elucidate transporter roles and downstream effects in disease pathologies. This and other resources created by plannedRESOLUTE are available for free on RESOLUTE’s website. This interagency effort promotes collaboration and interdisciplinary approaches, and helps to stimulate creativity and innovation in transporter research.
“What is the most important outcome is that we were able to annotate most, if not all, solute carriers with functional information and have created a vast arsenal of tools that now serve the global research community. This achievement, culminating in the RESOLUTE knowledge base, represents a unique resource and a true community treasure.”
The RESOLUTE project’s implications stretch well beyond its surprising findings. The discovery of new potential substrates for as yet uncharacterized transporters is set to spur exciting new directions for research and inquiry. The researchers hope that these findings will open the floodgates for transporter research. They hope this will stimulate an avalanche of new biomedical breakthroughs for decades to come.
Implications for Future Research
Giulio Superti-Furga expressed his gratitude for the support received throughout the project:
Giulio Superti-Furga expressed his gratitude for the support received throughout the project:
“We are deeply grateful for the support of the Innovative Health Initiative, IHI, (previously Innovative Medicines Initiative, IMI), a partnership of the European Federation of Pharmaceutical Industries and Associations, EFPIA, and the European Union, EU, and the contributions of all our outstanding partners—without whom this project would never have come to life.”
He further emphasized the unprecedented nature of this research effort:
“It is difficult to find in history a comparably ample and strong ‘push’ of enabling knowledge and tools towards an individual target class, so heavily involved in human disease. With these four studies, we hope to have lowered the barrier for transporter research and catalyzed a surge in biomedical discovery for years to come.”