Our innate immune system includes the complement system: some forty or so proteins circulating in the blood, where they clean things up and repel intruders. One of the major players is the C3 protein, present in the blood in very large quantities. But a handful of researchers across the world consider that C3 also performs important tasks inside cells. One of those researchers is Professor Anna Blom.

“Our experiments show that nearly all cells in the body produce C3, which seems to operate freely in the cytoplasm. But our fellow researchers have been highly skeptical. The last time I attended a conference I had to debate controversies in the field in a special session. People get quite heated. But if we’re right, and manage to persuade them of our hypothesis, I think this field will really take off,” Blom explains.

Protein a key cleaner

We already know that C3 plays an important part in autophagy, the cell’s process for breaking down its own proteins and organelles to get rid of damaged and surplus material. This process is disrupted in conditions such as type 2 diabetes, with less effective removal of insulin granules inside the cells that produce it.

“The cell needs to clean itself – just as we do when we take a shower in the morning. Autophagy is an essential process, enabling the cell to cope with stresses.”

Blom and her colleagues used human insulin producing beta cells left over after transplants. They were cultured in the lab, and exposed to inflammatory substances that are typical of diabetes.

“We could see that synthesis of C3 increased ten thousand times over – the protein was simply gushing out of them. We believe the cells were trying to increase their autophagy in order to survive.”

The researchers have used gene technology to breed mice that do not produce any C3 at all, and harvested their insulin-producing cells. They were exposed to sugar and fat to simulate an unhealthy diet and poor control over blood sugar levels. All beta cells die from such stress, but cells without C3 were found to die even more quickly than usual. The researchers are now breeding mice that lack C3 production only in their beta cells to see if they display a greater tendency to develop diabetes.

Potential unknown mechanism fending off infections

Blom is also studying the role played by the protein in infections, primarily in epithelial cells, found in the mucosae (mucous membranes) and the intestines. She believes that when bacteria manage to penetrate a cell, C3 can attach to them and cause the cell to destroy the intruder.

“We may have found a completely new mechanism used by the immune system to fight infection. We already know that C3 in the blood can bind to bacteria in a way that identifies them and triggers a response by the immune system. We think something similar happens inside the cells – that C3 recognizes what needs to be removed.”

It may be possible in the future to control the function to make it more effective. This would be helpful as antibiotics become less effective. Blom is extremely worried about antibiotic resistance. A few years ago her dog contracted a resistant infection and died. It really hit home to her how serious the situation is.

“Antibiotics still save millions of lives, but they are starting to lose their efficacy. When they do, it will be invaluable to find new systems and learn from our own bodies. After all, when we vaccinate ourselves we are exploiting the ‘acquired immune system’, but we don’t yet have any ways of stimulating its innate counterpart.”

Coping with setbacks

Anna’s mother was also a researcher. As a young girl, Anna often accompanied her to the laboratory, and she saw the passion her mother had for her subject. Following in her footsteps was not a hard decision to make. Anna was born in Poland, but moved to Sweden to study for her PhD.

“I liked the values here. If you do a good job in Sweden, you will receive funding, be given positions, and earn respect. There is very little corruption, and on the whole people treat each other well.”

“Being chosen as a Wallenberg Scholar is fantastic. The long-term funding I have received will enable me to pursue answers to difficult questions. There are no restrictions – I can use the money for animal experiments or wages or a new machine – which is just as it ought to be. My team is fantastic. Now we can really go for it and make a major commitment.”

This does not prevent the competition from frequently being intense. Already during her PhD studies she looked for a field that was not too crowded. She settled on the complement system, an interest so unusual that she has often had to work alone. So she is delighted to be collaborating more and more closely with researchers at the Lund University Diabetes Centre. They have patient samples, equipment and expertise that complement her own. Ten years ago Blom was ranked highest among those applying for a professorship at Karolinska Institutet, but she changed her mind and decided to stay in Skåne, in the far south of Sweden.

“You need a certain kind of personality to be a researcher. Most of what we do doesn’t work. Experiments don’t pan out as expected, articles get refused… So you need to be able to cope with setbacks. But I enjoy the freedom. I work really hard, but it doesn’t feel like a job.”

Having reached the age of 50 she has begun to plan what she will be doing over the next twenty years.

“I’m so curious. If a question pops up, I want to know the answer. But it’s important to focus on the most interesting issues; research does take such a long time. I hope this project will enable us to understand autophagy, and show that C3 defends against infections in every cell. I’ll be delighted if we succeed.”

Text Lisa Kirsebom
Translation Maxwell Arding
Photo Rebecca Rosberg