Thesis defense Gabriella Darmasaputra: Formation and function of binucleated human hepatocytes

For an entire human being to develop from one single fertilized egg cell, cell division is necessary. The cells in the human body generally have one nucleus, which contains the genetic material in the form of DNA. Before a cell divides, the DNA content in the nucleus is copied, to ensure that each new cell will contain the same genetic information. During normal cell division, the nucleus splits in two, after which each of these nuclei ends up in one of the two new cells. However, there are cells in the human body that contain more than one nucleus. Scientists do not yet understand exactly how binucleated cells are formed and what their function is.

Cell division time-lapse

During her PhD, Darmasaputra set the first steps in unraveling the formation and function of binucleated cells, which are cells containing two nuclei. She used hepatocyte organoids: mini-livers grown from human liver cells in the lab. “The liver is one of the organs containing a lot of binucleated cells. Therefore, it was a very suitable organ to study during my project,” Darmasaputra explains. While previous research was mainly able to take snapshots of dividing cells, and therefore only saw particular stages of the division process, Darmasaputra used microscopy to make time-lapses of the cells as they divided. This allowed her to follow specific cells throughout the whole process to see exactly how they divide. Darmasaputra: “We discovered that 5 to 15 percent of the dividing cells in these organoids acquire an extra nucleus due to a process called endomitosis. These cells go through most steps of normal cell division, including the formation of two nuclei, but stop before the entire cell actually divides in two. This results in single cells with two nuclei and therefore also double the amount of genetic material. This process of endomitosis was very consistent, suggesting that it is not random mistakes in the division of these cells, but a specialized program.”

Regeneration and cancer

The function of binucleated cells is still unclear and the subject of much research. “There are several things that could be related to it. The first is regeneration, which is the replacement or repair of damaged tissues. The liver is one of the few human organs that can regenerate and also contains a lot of binucleated cells. We are not sure if there’s a connection there, but hopefully future studies can give us a clue about this. Another interesting possibility to explore is the relationship between these cells and cancer. Binucleated cells do exist in the healthy body, but are also found a lot in cancer. However, it is still unclear what this means exactly. Does it contribute to causing cancer? Is it a consequence of cancer? We don’t know. Exploring this further could also help in finding new targets for cancer treatment,” Darmasaputra says.

Challenge yourself

Looking back on her PhD, the word ‘challenging’ comes to mind. Darmasaputra: “It’s really ups and downs. It was very challenging and I encountered myself in ways I didn’t expect. In the beginning, you come to work and you’re like: “Everything is going to fail”. And then after a few months, maybe you get a result. In the beginning, that’s super tough. You have to be really persistent. But now that I’m sitting here, I’m proud that I got through that and happy with how it went.” She was very happy with the support she received from her peers and supervisors. “It could have felt so lonely, but we talked about it with colleagues all the time and you know that everyone is going through the same thing. And I was lucky to have very supportive supervisors as well,” Darmasaputra says. Her advice to students who are considering doing a PhD? “A PhD is really about challenging yourself. You will encounter yourself in many different ways and I think that’s the point of it, really. If you think a PhD is the best way for you to challenge yourself, then go for it. But if you don’t, that is also fine. Just continue doing what you enjoy.”

Plenty of plans for the future

Darmasaputra has also taken that advice to heart herself. “Right now, I am still following my philosophy of “do what you think is fun at the moment”, so I’m currently working at the game shop Subcultures. One of the highlights of my PhD was that my interest in sharing science was piqued, so that’s also something I’m thinking about continuing. I have this dream that I want to make an art book about molecular biology, which I’m super excited about. But I have not ruled out academic science yet, so who knows, maybe I’ll be back,” Darmasaputra concludes.

Darmasaputra is throwing a party with family and friends to celebrate obtaining her PhD. Her family is coming over from Indonesia and she has invited friends from different aspects of her life to celebrate together.