Jiri Bartek and Jiri Luka
Professors Jiri Lukas from the University of Copenhagen, Denmark and Jiri Bartek from the Danish Cancer Society in Copenhagen and the Karolinska Institute in Stockholm, Sweden receive the Anders Jahre Medical Award for 2020 for their groundbreaking work in registering how proteins involved in the regulation of cell cycles and DNA repair contribute to protecting genes and preventing the development of cancer. Bartek and Lukas are both among the most frequently cited researchers in the Nordic region and their research has led to new principles in cancer treatment.
Before cells can divide, the genetic material must first be copied. Bartek and Lukas have demonstrated how this is carefully regulated through several checkpoints, where copying errors and other metabolic stress factors that can lead to DNA damage are registered and contribute to cell division pausing until the DNA damage has been repaired. This prevents the accumulation of dangerous mutations that can lead to cancer and other diseases. Based on these fundamental discoveries, Bartek and Lukas have further studied how these have changed in cancer cells, which has contributed to new therapeutic approaches and the development of advanced technology that can be used diagnostically in cancer treatment.
The work of Jiri Bartek, often shared with Jiri Lukas over many years, has focused on better understanding of two fundamental, and mutually connected cellular processes, namely mechanisms that control cell division, and those that protect our genes, the blueprint of life, from potentially hazardous changes that could leave to developmental defects or cancer. Jiri Bartek and colleagues discovered several so-called cell cycle checkpoints: molecular mechanisms that ensure that our cells sense and respond to various signals about their environment and any stressful conditions, such as impact of radiation, cigarette smoke, excessive sun exposure or some toxic chemicals that all can damage our DNA and possibly accelerate the process of aging or even lead to cancer development. A special area of interest during the cell division cycle, studied by Jiri Bartek and colleagues, is the process called DNA replication – in which each cell before it divides must accurately and completely duplicate their entire genome. Proper and error-free genome duplication is a prerequisite for normal organismal development and tissue and organ renewal and function. At the same time, DNA replication is also challenging for the cells due to many potential obstacles on DNA that may slow down or block the process, causing a state of emergency called replication stress. Mistakes in either replication or response to replication stress can cause abnormally high or too little cell proliferation, and lead to life-threatening diseases such as developmental defects, premature aging or tumor formation. Based on their fundamental insights into cell cycle control and cellular responses to DNA damage, the Bartek team then studied the differences in these processes between normal and cancer human cells, and found several abnormalities of tumor cells that on one hand fuel cancer progression, however on the other hand create a state of enhanced stress selectively in cancer cells, that makes tumor cells more addicted to some mechanisms of survival, a concept pioneered by Jiri Bartek in that such dependencies can be exploited as cancer vulnerabilities in innovative cancer treatments. Jiri Bartek and colleagues found several such cancer cell vulnerabilities and also suggested ways these addictions, indeed potential ‘Achilles heels’ of cancer, can be turned against cancer, such as blocking the ability of abnormal cancer cell cycle to slow down or repair their DNA, eventually causing excessive damage and death of cancer cells, while sparing normal healthy cells. Apart from the contribution on the basic, mechanistic level of understanding cell function and abnormalities of cancer cells, Jiri Bartek and colleagues also helped to understand why some cancer cells are resistant to currently used standard of care treatment modalities such as ionizing radiation or chemotherapy, found some ways how to overcome such treatment resistance, and suggested biomarkers to help oncologists to guide proper selection and monitoring of cancer therapy in the future.
Jiri Lukas made groundbreaking discoveries about how DNA repair proteins organize themselves into signaling pathways during the cell division cycle and how these pathways functionally communicate with cellular metabolism to preserve genome integrity over many generations of dividing cells. His work laid down the foundation for understanding of how malfunctions of these mechanisms leads to diseases marked by unstable genomes, namely cancer. His major discoveries include identifying a stress-induced signaling pathway that stops cell proliferation before they acquire dangerous mutations, elucidating how chemical protein modifications regulate repair of cancer-promoting DNA lesions, explaining the role of DNA replication stress in causing heritable damage to human genome, and identification of limiting DNA repair proteins to which cancer cells become addicted and which can thus be exploited as drug targets. The Lukas laboratory is also renowned for pioneering advanced single-cell imaging techniques including three-dimensional reconstruction of damaged chromosomes by super-resolution microscopy. These discoveries illuminate fundamental principles of cell proliferation under stress and generate powerful resources of previously unknown molecular caretakers that guard the integrity of human genome against cancer-predisposing aberrations. In the big part of his professional career, Jiri Lukas has created a remarkable scientific partnership with his namesake and close colleague Jiri Bartek. Their decades-long collaboration culminating at placing the DNA replication stress amongst the hallmarks of cancer is the lasting example of how beneficial scientific synergy can be for unraveling major mysteries of cell division with direct implications for understanding cancer etiology and treatment.