The Jahre Lectures 2024

Abstracts

Nicolai Jacob Wewer Albrechtsen: ¡°Glucagon role in metabolic diseases¡±

Glucagon is a peptide hormone secreted during every meal you eat. Since the discovery of glucagon 100 years ago, the focus has been to understand how glucagon regulate glucose homeostasis and how increased circulating glucagon contribute to diabetes development. We and others have repositioned glucagon as a hormone with diverse metabolic importance for not only glucose but importantly also protein and lipid metabolism. The two later has direct clinical consequence with the introduction of new therapeutics targeting glucagon signaling.

The focus of my talk will be to address a conceptual new frame for glucagon biology known as the liver-alpha cell axis and how this physiological feedback system is disrupted by obesity causing a diabetogenic state and finally the discovery of a new terminology in physiology, glucagon resistance.

Nicholas M I Taylor: ¡°Molecular machines at the cell membrane: from structure to function¡±

:All life depends on cells, such as the trillions of cells that make up our bodies or the bacterial cells that help digest our food or infect us. The barriers and interfaces of these cells are phospholipid membranes that shield interior from exterior. 

I am interested in understanding how protein-driven molecular transport occurs across the membrane. For this, we use a technique known as cryo-electron microscopy to investigate these transport proteins at very high resolution. We can then model their atomic structures. If we can visualize different structural states, we can make molecular movies for how these proteins function.

I will present two cases where this was successful. A first one are studies on human multidrug resistance protein overexpressed in cancer, understanding of which can lead to better anti-cancer treatments. The second case is our work showing how bacteria move, which could contribute to development of future novel antibiotics.

Lauri Aaltonen: "From genetic predisposition to molecular mechanisms; lessons from colorectal cancer and uterine leiomyoma"

The notion that tumors arise through (epi)genetic aberrations is currently well established. Thus, it is not surprising that research on hereditary genetic susceptibility has provided important contributions to medicine. In fact, one of the first unbiased genomewide cancer research strategies was based on large families segregating malignancy in a tissue specific manner. Even in the absence of high-throughput technologies it was possible to scrutinize the genome for localization of key genes predisposing to cancer through linkage analysis. Our efforts in colorectal cancer as well uterine leiomyoma are reviewed here. In both cases, the early findings on susceptibility genes have been successfully translated into a profound understanding on the respective molecular mechanisms, as well as breakthroughs towards tumor prevention and personalized management. This has required a vast amount of effort, and many co-workers and collaborators. The willingness of the patients to participate in this work has been instrumental to its success.

Thomas Helleday: ¡°Targeting the recombination repair defect in tumour suppressors with PARP inhibitors¡±

Damage at DNA replication forks are central to both cancer development and treatment. Here, I describe how different DNA repair pathways collaborate at replication forks and how this is key for cancer cell survival and suppressing mutations and cancer development. This work led up to the identification of the synthetic lethal concept; treating BRCA1 or BRCA2 mutated homologous recombination defective cancers with PARP inhibitors. I describe the early pre-clinical and clinical challenges in developing this concept into the clinic. I also describe how a clinical question from a curious young urologist led, through backtranslation, to novel basic science insights into how the androgen receptor controls DNA repair. We could use this basic science information to hypothesize and identify a novel treatment for prostate cancer that recently was approved across the world and represents the first drug-induced synthetic lethal strategy in treatment of cancer.