Danish physicist Mathias Heltberg of the University of Copenhagen, together with world-leading Harvard Medical School researchers, has discovered what controls the body’s most important tumor suppression mechanism. The result is a major step forward towards understanding and preventing cancer. The new knowledge could even be used for detecting problems within cells before cancer develops.
No, it’s not a type of World War II fighter plane. p53 is one of the most important proteins for controlling cells and combatting cancer. When DNA becomes damaged, p53 responds by informing every cell in the human body that cell division must cease until the damage has been repaired. For this, p53 has been called “the guardian of our genome”.
“While this is one of the most important mechanisms for avoiding the spread of tumors, we still don’t know much about how it is controlled,” explains Mathias Heltberg, 29, a theoretical physicist and postdoc at the University of Copenhagen’s Niels Bohr Institute and École Normale Supérieure in Paris.
In a new study, the young researcher, in collaboration with fellow UCPH physicist Professor Mogens Høgh Jensen and Harvard Medical School researchers, has made the world a a bit wiser. By mapping a network of proteins that controls the behaviour of p53, the researchers have demonstrated that yet another protein, known as MDMX, is the so-called ‘master regulator’. That is, a protein that, more than others, determines how p53 behaves in cells. This had been an area of uncertainty.
“More accurately than ever before, we have identified how MDMX behaves within this incredible network of proteins. We have demonstrated that MDMX causes the concentration of p53 in our cells to fluctuate over time, and in doing so, is involved with determining how well a human body is able to combat tumors.”
Regulating the tumor-suppressing protein
To study how p53 would be affected, researchers deployed a mathematical model in which they removed the MDMX protein from cells. Their observations revealed a surprising behavior: cells suddenly exhibited a high concentration of p53. In other words, the p53 was called to attention, much in the same way as it would be if repairing damaged DNA. In the absence of MDMX, there is nothing to hold the p53 protein in check.
“It is a perfect regulator. Having too much p53 is not necessarily good, but it is very important for p53 to stay at correct levels in order for it to function as it should. This is where MDMX plays a crucial role,” explains Mathias Heltberg, whose colleague Mogens Høgh Jensen adds:
“It is the first study to prove directly that MDMX helps degrade p53 in order to regulate p53’s concentration under normal circumstances. At the same time, the study also allowed us to reject previous hypotheses regarding the relationship between p53 and MDMX.”
About the study:
- Using mathematical models and experimental measurements of the concentrations in p53, the Niels Bohr researchers have demonstrated that the tumor-suppressing protein p53 is regulated by the MDMX protein.
- Using mathematical models, the researchers removed the MDMX protein from cells. Thereafter, a high concentration of p53 appeared. In this way, they were able to determine that MDMX has a regulatory or stabilizing effect on p53
- p53 plays a key role in repairing damaged human DNA. p53 responds to DNA damage by calling for a halt to all cell division in the human body, until the damage has been repaired.
- The study was conducted in collaboration with a Harvard research group that is pioneering the understanding of the protein p53’s role in cancer diseases.
World-leading research group is thrilled
The study was conducted together with a Harvard research group that is pioneering the understanding of protein p53’s role in cancer diseases. Mathias Heltberg spent six months of his PhD programme at Harvard Medical School, from where the collaboration emerged. It is a collaboration that, according to Heltberg, has only just begun.
“The research group has been enthusiastic about our approach to the subject and we expect to be doing a lot of work with them in the future,” he adds.
But how does a physicist fit into cancer research?
“As far back as Niels Bohr, physicists have been interested in biology and the study of living things through mathematical descriptions. There is great complexity in understanding the fundamental regulatory processes of cells. Through mathematical and physics methods, we are able to study nature and see how many different elements interact through, a network of proteins, for example,” says Heltberg.
From football to cancer-related research
In 2019, Heltberg won the University of Copenhagen’s award for best scientific PhD dissertation. The dissertation, “Complex Dynamics in Cell Signalling”, focuses on the dynamics within cells when, for example, protein p53 achieves a high concentration that then begins to fluctuate.
At the time, cancer-related research was not in the cards for Mathias. During the study, he spent a lot of time as a football coach and focusing on particle physics. This all changed during his collaboration with biocomplexity researchers at the University of Copenhagen. With them, he discovered creative inspiration and the opportunity to work on fundamental issues related to “the living”.
Mathias is currently a postdoc at the École Normale Supérieure (ENS), France’s premier institution for higher education and research. Here, his research focuses entirely on the molecular processes at work when DNA becomes damaged.
“The dream is to be able to make a positive contribution to Danish research and create a few unique frameworks for anyone with an interest in studying nature. I have worked with top researchers from Europe, China, India, Israel and the United States, but to be completely honest, I feel that the most inspiring place to be is the environment at the Niels Bohr Institute on Blegdamsvej. It truly is a world-class university environment,” concludes the young researcher.