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Work requiring a lot of patience: Having separated fragments of DNA from cancer cells, members of Massimo Lopes’s team sit for hours in a darkened room observing them under an electron microscope. What the young scientists are seeing is real snapshots of genetic activity: Points in the genetic substance where the double strand of DNA is in the process of duplicating in preparation for imminent cell division. Lopes is convinced that these points hide a key that could make cancer therapy substantially more effective.
Massimo Lopes, assistant professor at the Institute of Molecular Cancer Research, explains that the division and subsequent replication of double strands of DNA is a crucial element in cell division. Cells can’t divide until the chromosomes in their nucleus have replicated. This mechanism is particularly important for cancer cells, because they divide so frequently. “One of the key features of cancer cells is the way they replicate unchecked,” says Lopes. “That’s why so many cancer drugs target this process, aiming to stop the DNA from replicating and prevent the tumor from growing further.”
Scientists are only just starting to understand how cancer drugs intervene in the replication process to disrupt the sophisticated mechanism in the cell nucleus. It’s therefore impossible to say exactly why certain drugs work better than others for specific types of cancer. “Chemotherapy is still largely based on empirical observations,” explains Lopes. “This was something that astonished me already while I was studying for my degree.” Lopes wants to change this by showing step by step how DNA is replicated. He has a major initial milestone to report: He and his group have discovered a mechanism that could explain why cancer drugs don’t always work as well as hoped.
To understand this means taking a closer look at the processes occurring right before actual cell division. This phase involves a really clever process for replicating the DNA in the cells: The double strand is opened from one end like a zip. Immediately behind this opening the two individual strands are copied, resulting in two complete double strands of DNA. At places where the genetic substance is in the process of replicating a typical “fork” structure appears: on one side of the fork is the part of the DNA strand that still has to be replicated, and on the other side the two new copies. It’s these three-armed shapes that Lopes’s team is looking for under the microscope.
Lopes uses an everyday comparison to describe the process: “This replication mechanism is like a train running down a track. The basic idea of chemotherapy is to place obstacles on the rails to prevent the train from going any further.” In terms of DNA, what’s happening is that the cancer drug molecules are changing the existing DNA double strand to such an extent that the copying process is blocked.
And of course because cancer cells replicate so frequently, their molecular “trains” are especially affected by these obstacles. But these “tracks” are also blocked in healthy cells. This is particularly fatal for cells that renew frequently, for example hair cells or cells in the mucous membranes. Cancer drugs also prevent these cells from dividing, which is why patients lose their hair during chemotherapy.
Now Lopes has found out that cancer cells have a sophisticated defense mechanism that reduces the effect of cancer drugs. As well as ensuring that the molecular trains stop when they encounter an obstacle on the line, this mechanism enables the cells to put the track back in order. In other words, the repair mechanism rearranges the DNA strand so that the replication process can continue.
The means by which this happens is astonishing: when the repair mechanism notices a problem at some point in the DNA strand, the replication process is interrupted and continues in the opposite direction, with the new, unblemished double strand used as the basis for replication instead of the imperfect section. This appears as a double fork under the microscope: instead of a three-armed figure, you suddenly see a structure with four arms.
On one side of the fork is the portion of DNA that has not yet divided; on the other are the other three arms, two of which are the new copies, and the third composed of new sections of strand. The problem spot is avoided by using the perfect new strand as the basis of replication instead of the old double strand. By means of this correction, cells can resume the original copying process. Or as Lopes puts it, new track is laid around the obstacle to enable the train to continue down this section of line.
This process is apparently a fundamental repair mechanism: “When we examine cancer cells that have been treated with cancer drugs we find four arms in between one third and one quarter of the forked DNA fragments,” explains Lopes. It’s worth noting that back in the mid-1970s scientists were already suggesting that cells could correct for defective DNA in this way. But although the idea was illuminating, it seemed too complicated and wasn’t pursued any further. At that time it couldn’t be verified experimentally either. Only now, almost forty years later, has Lopes been able to show that this really is how the repair mechanism in cells functions.
These new insights give Lopes a good basis for further research. To support this research he was awarded a CHF 2.3 million ERC Consolidator Grant by the EU at the beginning of this year − just before the Swiss electorate voted for the mass immigration initiative, as Lopes notes with a wry grin. In collaboration with partners from other European countries he now wants to find out how to systematically disrupt the corrective mechanism in cells. “If we’re able to outwit the defensive system in cancer cells we might be able to reduce the number of obstacles we have to lay to prevent trains from traveling further. In other words, we could cut down the dose required for chemotherapy, and reduce the side-effects.”
