Breakthroughs in COPD research

To one day cure COPD, a group of top scientists in Europe and the United States have been working together for five years. They have already produced some great results. "Enough to move forward", says US scientist Carla Kim.

Seven years ago, Longfonds started an initiative to accelerate a medical breakthrough for COPD. Longfonds, therefore, brought together top researchers from around the world. Longfonds director Michael Rutgers sought contact with Hans Clevers. Along with Carla Kim, this Dutch stem cell researcher arranged for specialised researchers from the United States, the United Kingdom and the Netherlands to work together. This led to LONGFONDS | Accelerate.

Understanding what goes wrong

Five years ago, the BREATH project started within this collaboration. It stands for Building Respiratory Epithelium and Tissue for Health. Or 'fixing broken lungs'. "We hope to be able to cure COPD in the future", says Carla Kim, the US scientist in charge of the day-to-day management of the research programme. 'When we started BREATH, the World Health Organisation (WHO) predicted that COPD would be the third leading cause of death worldwide by 2030. That turned out to be true as early as 2019, years earlier than expected'.

By working together, we move faster. But good research takes time, Kim stresses. "A lung is a complicated system. To cure COPD, we need to understand exactly what goes wrong in a COPD lung. We know that the pulmonary alveoli break down irreparably. 'The challenge of our research project was to repair this damage in the future".

The BREATH project is divided into four sub-projects

The four sub-projects are taking place simultaneously. And knowledge is constantly being exchanged, which is the unique feature of this collaboration.

• 1. What goes wrong in a COPD lung

  Kim: "We know what symptoms a COPD patient has. But we don't know exactly which cells cause someone to get COPD. To find out, we compare a healthy lung to a COPD lung. Are certain types of cells absent? Are different cells present instead? In other words, what is different in the COPD lung?'

• 2. What does it take for a cell to grow

  Kim: "In COPD, the cells that exchange oxygen do not function properly. A lung stem cell makes new cells grow. What does such a lung stem cell need to grow these very cells in the lab? We find out which chemicals are suitable for it. So that we can later develop a medicine that can switch these cells on, so to speak'.

• 3. Can cells cultured in a lab be placed in a human lung

  Carla Kim herself is investigating whether cells cultured in a lab can be placed in a human lung. And do what they are supposed to do there. To test this, this project involves working with mice. "We let lung stem cells from a mouse grow into a kind of mini-lung in the lab. We insert its cells into another mouse. If all goes well, these cells become part of that other mouse's lung tissue".

• 4. Where all the knowledge comes together

  Here, researchers look at how to create a new lung with all the parts (the cells). It's not just about the cells on their own, but also the structure. Compare it to a 3D puzzle: for it to be correct, each puzzle piece has to be in the right place.

Kim gives a few examples: "Because we find out which cells in a COPD lung do not work (sub-project 1), in sub-project 2 we can look at how to get those cells working.   If we introduce these cells into a mouse (sub-project 3), we might need a drug to stimulate it (sub-project 2). And if we know how to transplant cells (sub-project 3), then in sub-project 4 we can determine the structure".

Biomarkers

In this final year of the BREATH project, the researchers take stock of the situation. What has been achieved in those five years? Enough to take steps forward, says Kim. Researchers in Pennsylvania discovered a new type of stem cell (RASC). This allows lung alveoli cells to grow. "Then we noticed that in a COPD lung, there are many more RASC cells than in a healthy lung. They failed to transform from stem cells to epithelial cells (a cell used to line the lung, ed.) But they do contain the biomarkers we so desperately need. A biomarker is a cell that shows what is happening in the diseased lung. The Pittsburgh lab also discovered a whole series of such biomarkers that indicate COPD. So with these discoveries (from sub-project 1, see box, ed.), we better understand what is wrong in a COPD lung'.

Existing drug

Dutch researcher Reinoud Gosens made a discovery with a fellow researcher in Pittsburgh in the second subproject. What does it take for a cell to grow? They discovered in the lab that lithium, an existing drug, also affects COPD. This drug is often used by people with mood swings. The communication between cells and molecules in people with COPD does not function properly. Simply put, a cell does not understand what it is supposed to do. Lithium ensures that that process does run smoothly'.

Now the researchers will look for people who use lithium for their mood swings and who also have COPD. If it turns out that this group suffers less from COPD, a trial can start to see whether people with COPD are helped by lithium.

Mini-lung  

The third subproject is also going according to plan, says Kim. Like growing a mini-lung from a healthy mouse in the lab and transplanting its cells to another mouse. So where do we go from here? "We now know that it is possible to do this between two healthy mice. But will it also work if we transfer these cells to a mouse with COPD? That turns out to be more challenging. We need to find out what is needed to make those cells work in a COPD mouse. That's where the knowledge from the first sub-project helps. After that, we can start looking at how we can use human cells'.

The solution may lie in London. Work is underway there to build a new lung. The researchers developed a type of gel from lung tissue. If this gel has just the right structure, it can support the growth of lung cells. Kim: "We are now going to see if this gel can help the cells in the COPD mouse to grow. This is how different sub-projects come together'.

Snowball effect

Kim is enthusiastic about the results BREATH has produced so far."As we increasingly understand COPD, we will start making a difference. Consequently, we will also have more opportunities to help patients. The great thing is that we are focusing on two developments: drugs and cell therapy'.

"Due to this international collaboration, scientists around the world are now working together to repair a damaged lung. That creates a snowball effect. Thus, the disease gets more attention and we will reach even more excellent results. And that is desperately needed'.