“Even though I’m a professor now, I still spend a lot of time in the lab, because I know that when I’m at the microscope, working with my hands, that’s when I get new ideas,” says Peter Nielsen, organic chemist at Linköping University (LiU) in Sweden. Professor of Science. It develops tracer molecules that can recognize different proteins. The molecules are used in research, such as in Alzheimer’s disease. Interdisciplinary collaboration is one of the keys to her success.
Jimi Hendrix looking down at us from a shelf in Peter Nielsen’s office, a cigarette in the corner of his mouth. A small electric guitar in front of him indicates the type of music often played here. Music has played a role in Peter focusing his research on neurodegenerative diseases that destroy the brain. Many such diseases are linked to proteins that accumulate in aggregates that can damage cells.
“As a PhD student, in the early 2000s, I was tasked with experimenting with the precursors to the tracer molecules we have today. I sat in the lab, listening to hard rock. That’s how I met Per Hammarström, also a hard rock fan, who was recently postdoctoral in San Diego. was back at LiU. He was working on protein aggregates. We started talking about molecules and realized that wow, they could probably be used in protein aggregates.
More than 20 years later, they are still close colleagues. Building strong bonds seems to be a recurring theme for Peter Nielsen. Growing up, he was drawn to team sports, and now sees research as a team effort as well. He is inspired by people who build great teams who manage to achieve more than they ever imagined.
“Collaboration is what makes science fun. Together, we’re coming up with things we can test in the lab.”
Chameleon molecules change color
When Peter Nielsen began working on tracer molecules, they consisted of small chemical units that formed themselves into long chains, called polymers. Since then, researchers have recreated the tracer molecules with molecular precision, so that they know the exact location of each atom.
“Every new step we take involves more organic chemistry. Polymers, which build themselves up, work well to see things in test tubes. But if we want to use them for diagnosis and treatment, the tracer molecules have to be very specific and able to find one particular molecule among thousands,” he says.
The ability of a tracer molecule to recognize specific proteins makes it useful for researchers worldwide. Once the tracer molecule finds its target protein, it binds to it and, thanks to its bendable spine, can mold it. The clever thing is that when the researchers shine a light on the tracer molecules, they glow again. This phenomenon is called fluorescence. Depending on the twist of its backbone, the molecule can take on different colors. Thanks to this, researchers can study the shape of damaged protein aggregates, which may be important for understanding Alzheimer’s disease and other types of dementia.
Aim for patient benefit
Once LiU researchers find a molecule that works well, they modify it in various ways, not only to make it work better, but also to understand exactly which details of it are necessary for its function.
“What we’re seeing is that very small changes in the tracer molecules have a big impact on their function,” says Therese Klingstad, senior research engineer at the research group, which uses tracer molecules in tissue cuts to see what protein aggregates look like.
They are now developing tracer molecules that bind only to the aggregates found in Alzheimer’s disease, and not to the same plaques in closely related diseases. This opens up the possibility of using tracer molecules in humans, to detect harmful protein aggregates and give a specific diagnosis.
“We’ve found molecules that we want to develop for diagnostics. We can label the molecules with radioisotopes so they can be detected using hospital PET scans. I think within the next 5-10 years, we’ll be able to develop molecules that can be tested for diagnostics. We can,” says Peter Nielsen.
In the last few years, researchers have seen that tracer molecules can also potentially be used as therapies. A recently published study EMBO Nuclear Medicine, used mice with Alzheimer’s-like disease, where misfolded variants of the amyloid-beta protein accumulate to form brain plaques. Misfolded proteins can convert normal variants into harmful forms, thereby increasing the amount of protein aggregates. In a study led by researchers from the University of Zurich, mice that received the LiU researchers’ tracer molecule had less amyloid plaque. Researchers believe that a fateful chain reaction is interrupted when tracer molecules bind to harmful protein aggregates.
“Unlike other treatment strategies being investigated for Alzheimer’s disease, our molecule appears to work in mice of different ages, not just in young individuals. This is interesting, as it is thought that the aggregates that form in neurodegenerative diseases form about ten years before any symptoms appear. .So it’s interesting to find treatments that can potentially work even when the process is long-standing and when the disease is diagnosed,” says Peter Nielsen.
Peter Nielsen enjoys international interdisciplinary collaborations with researchers at, for example, Indiana University, the MRC Laboratory in Cambridge, the University Hospital of Zurich, and the German Center for Neurodegenerative Diseases.
“These collaborations include researchers in theoretical physics, organic chemistry and medicine. We are at the center of it and can talk and understand researchers from different fields. We often act as scientific translators between participants in different projects.”
He has participated in many of these collaborations for over ten years. Continuity is important. Through their postdoctoral periods abroad, the group’s researchers have built a network that lives on.
“In interdisciplinary collaboration, the boundaries between chemistry, physics and medicine are blurred. I personally enjoy learning new things from others. For interdisciplinary collaboration to work, you have to be able to say “I don’t understand this” and then have your colleagues explain it in another way. , so that we can actually talk to each other. It can be a little difficult sometimes,” he says with a laugh.
He also believes that another success factor in this collaboration involves exchange.
“We send them molecules and they send us tissue and material, which helps us develop tracer molecules. This exchange enables us to do a lot more. We can confirm each other’s data and we also find new things to study more closely.”
Interdisciplinary collaboration leads to new research ideas. Peter Nielsen returns to the idea that it is important to have the courage to keep trying new things.
“In our field of research, it’s all about doing experiments. A lot of times you don’t think it’s going to work, but then you look at an experiment and you see an unlikely result – something you couldn’t predict. It’s by experimenting that you get things to investigate further. Even though I’m a professor now, I still spend a lot of time in the lab, because I know that when I’m at the microscope, working with my hands, that’s when I get new ideas.
Article on EMBO Nuclear Medicine: Whole Brain Microscopy Reveals Differential Temporal and Spatial Efficacy of Anti-Aβ Therapies Daniel Kirschenbaum, Ehsan Dudgar-Kian, Francesca Cato et al, EMBO Mol Med (2023) 15:e16789, https://doi.org/10.15252/emmm.202216789