Manipulating Protein Factories

It’s a factory that never shuts down: millions of proteins are produced in our cells every single day. We need them as building blocks to create almost everything we need, from muscles and hormones to antibodies for our immune system. The proteins are assembled by the ribosomes – the protein factories in our cells.

“As important as this process is, there are many aspects of it that we still don’t fully understand in detail,” says Ataman Sendoel, professor at the Institute for Regenerative Medicine at UZH. He’s spent the last 13 years dedicating himself to researching protein synthesis. His interest in this area began when he was doing research with nematodes as a doctoral candidate at UZH. Ever since, there’s been one question he’s been determined to find the answer to: what role does the production of proteins in our cells play in determining whether we stay healthy or get sick?

Over the next five years, Sendoel will be able to systematically explore this question, thanks to a Consolidator Grant that he has been awarded by the European Research Council (ERC) of the European Union (see box). 

Proteins are produced in our cells in a two-stage process. First, our genetic material is read and the DNA is copied bit by bit into the messenger substance mRNA. Then the ribosomes get to work. They attach themselves to the mRNA, read it and use this blueprint to assemble amino acids into proteins.

Proteins are large molecules that are made up of different amino acids. We get a large proportion of these amino acids from the food we eat. It’s estimated that the ribosomes in each cell produce hundreds of thousands to several million proteins every minute. At the same time, proteins that are old, damaged or no longer required are broken down – and recycled to produce new proteins. A large proportion of the proteins in the human body are continuously renewed – some of them within hours, others within days or weeks.

A number of things can go wrong in this process. Ataman Sendoel is particularly keen to find out what role protein synthesis plays in cancer. That’s because we now know that tumor cells can manipulate the protein synthesis in the cells – in such a way that it aids further growth of the tumor or helps it withstand chemotherapy, for example. But scientists still have very little idea of exactly how this happens. Sendoel wants to help to clarify this as part of the ERC project.

His research group will be focusing on two types of tumor cells. It will look firstly at normal cancer cells and secondly at cancer stem cells, whose technical medical term is tumor-initiating cells. Just like healthy tissue, tumors also have a type of stem cells. They’re particularly long-living, divide more slowly and this makes them more resistant to therapy than other tumor cells.

Depending on the type of cancer, there’ll be more or fewer such stem cells in a tumor. In the case of cancer of the pancreas, for example, they account for a high proportion of the cells. So it’s no wonder that this type of cancer is better able to regrow following treatment. “This is why it’s important to gain a better understanding of cancer stem cells in particular so they can then be fought with more targeted treatments,” says Sendoel.

To do this, it’s important to investigate a process that is still largely not understood – the transition from healthy to cancerous tissue. What’s clear is that it starts with mutations in healthy cells that then begin to divide in an uncontrolled way.

Protein production plays a key role in this. “Proteins have a crucial bearing on what happens in a cell. And so they also determine whether a tumor grows, whether it forms metastases and how it responds to therapy,” says Sendoel.

So his project is all about answering the key question: how does protein synthesis that occurs in healthy cells differ from protein synthesis that occurs in cancer cells and cancer stem cells?

One particular aspect that was discovered just a few years ago may well play an important role in this, namely that in the cells not every mRNA is uniformly converted into proteins – some mRNA is selected for this over other mRNA. So a major difference between healthy cells and cancer cells may well be which mRNA they translate.

“Tumor cells will primarily convert those mRNAs into proteins that serve their purposes. What we want to find out is which processes they control,” explains Sendoel. What we already know today is that a whole network of participants is involved in this control process. RNA-binding proteins are particularly important. They attach themselves to the mRNA and play a key role in determining whether it’s read by ribosomes.

Ataman Sendoel’s research group is studying protein synthesis primarily using a mouse model. The fact that it’s actually possible to explore these molecular processes is down to new technologies, which Sendoel’s research group has helped to develop. They now enable researchers to watch ribosomes at work.

This technique is called ribosome profiling and essentially it involves freezing the ribosomes to get a snapshot of their activity: Which mRNA is currently being processed into proteins?

Previously, this was done using entire cell populations to obtain a picture of the average. Advances in technology mean that today it’s also possible to record what happens in individual cells. This is particularly important for comparing different cell types within a tumor.

As part of the ERC project, the team led by Sendoel will keep developing the technology it needs to do its research. Until now, it has only been possible to visualize the production of mRNA and the production of proteins separately – because the techniques required to do so are so different. “We want to try to integrate the approaches so we can observe the two processes in one cell simultaneously,” says Sendoel.

Ataman Sendoel is one of nine researchers from UZH to be awarded a Consolidator Grant by the European Research Council (ERC) in December 2025. These grants help researchers conduct ambitious research projects, establish or strengthen their own research teams and advance their scientific careers.

Even though many questions in relation to protein synthesis remain unanswered, Ataman Sendoel’s research has already yielded valuable findings. For example, the focus used to be on the large proteins that are produced in a cell.

But researchers have now realized that countless small proteins are also produced in the cells. Ataman Sendoel was one of the people involved in discovering these microproteins. The ERC project at UZH is also keen to provide answers to the question of what their function is.

The study of protein synthesis is primarily basic research. But it also opens up new potential therapies – for treating cancer, for example. Although there aren’t yet any corresponding drugs, the first clinical trials are underway.

When Ataman Sendoel worked as a postdoctoral researcher in the US, he established the basis for a potential therapeutic application. He discovered a protein that acts like a switch: it alters the protein synthesis in skin cancer in such a way that it promotes tumor formation. Sendoel is now collaborating with his former university to try to find active substances that will block this switch.

“Basic research is extremely important. We never know before we start what results we’ll obtain. But as a physician, I’m always thinking about how new findings could benefit patients in the long term,” he says.

To do this, the key thing is to identify the weak points of protein synthesis in tumor cells. One challenge will be to influence specifically just the protein production in these malignant cells, but not in healthy cells in the body. “We need smart solutions to prevent any side effects, because protein production takes place throughout the body,” says Sendoel.

This is exactly what ERC Consolidator Grants are intended for – projects that can be categorized as “high risk, high reward”. Researchers should be able to pursue unconventional paths that will produce completely new insights if they are successful. Ataman Sendoel is grateful to have been given financial security for the next five years. This will enable him to establish a team – and the best-case scenario is that he’ll be able to clarify key questions about protein synthesis in tumors.