‘Chances are a surge of knowledge is coming’

For treatments to arise, more basic knowledge is needed about COPD. To acquire this, top scientist Oliver Eickelberg put together a research team thatwas the first in the world to map the proteins in the lungs. “I feel it is my duty to help patients as fast as possible.”

“I have been a physician-scientist for decades. Still, after all these years, the moment I realise we have discovered something new, is very exciting. But when other labs reproduce and validate our results, that’s when the excitement really kicks in,” says Oliver Eickelberg, renowned Professor of Medicine at the University of Pittsburgh (US) and lead scientist in the Lung Regeneration Consortium. “Every experiment you do, is basically a conversation with nature. It does not always give you the answer you expect. But it always brings you further.”

This is very much needed. COPD is the third leading cause of death worldwide and current treatments only relieve the symptoms. “Many people don’t realise what it is like to have a severe lung disease. Having limited breathing capacity, limits all aspects of your life. And imagine the frustration of walking around in air, but not being able to take it in.”

Neglected child

The goal of the Consortium is to treat the underlying causes. For this to happen we need to know: how does the damage occur? What happens in the cells and on a molecular level? This is not yet known. Eickelberg: “COPD is the neglected child of biomedical research. It likely affects more people than other severe lung diseases combined. The mechanisms of many of those diseases are known. We have made significant progress in areas such as lung cancer and cystic fibrosis, but not in COPD.”

Unravel hallmarks of COPD

To change this, Eickelberg unravels the hallmarks of COPD. His group focusses on the extracellular matrix (ECM): the mixture of proteins, that function like a 3D-scaffold for all tissues, including the lungs. To explain the importance of ECM, Eickelberg draws a parallel with the skin. Young skin is elastic, flexible and strong. This is because of the extracellular matrix. As we age the skin loses its flexibility due to changes in the composition of the extracellular matrix. “In COPD a similar process occurs in the lungs. It results, amongst other things, in alterations in the 3D-structure and stiffness (emphysema). As the ability to expand is key to lung function, this is why the ECM is important.”

Eickelberg wants to be able to regenerate damaged ECM. To do this he needs to know the basic role this matrix plays in COPD. What cellular components, molecules and signalling pathways of the cells are involved?

Proteins regulate tissue function

For this he studies the set of proteins (called the proteome) present in the ECM of lungs. Proteins are interesting because functionality of any tissue is based on the chemical processes and signalling pathways in it: most of these are carried out by proteins. “So knowing the proteins involved, shows us the signalling pathways. But this demands a precise 3D-map of which proteins are present, how much and where exactly in the organ.”

From DNA to RNA and protein

Until recently the standard approach was to compare COPD-ECM to healthy tissue. And to use measurements of RNA to determine the proteins present. “The hereditary information on the  DNA gets transcribed into RNA. And this is translated into a protein. That is why scientists thought the amount of RNA correlated with that of proteins. But it was discovered that this correlation is incorrect, and many RNA-protein correlations are in fact poor.”

‘Thankfully we succeeded’

So, Eickelberg set himself to the task of mapping the proteins themselves. “It took a significant effort to create a team that allows this proteome mapping. Proteins are less stable and much more difficult to accurately measure then RNA. Thankfully we succeeded, as the first in the world.”

Different approach

And more progress is coming. Eickelberg is now comparing the proteome of COPD tissue not only to healthy tissue, but also to lung tissues with a wide range of diseases. “This is a completely different approach that leads to much more information – and understanding of COPD.”

Dutch cuisine

Eickelberg clarifies with another analogy. Let us assume you’d like to know the hallmarks of Dutch cuisine. You might compare it to the German cuisine. The differences will be labelled typically Dutch. Eickelberg: “You will probably find that cheese stands out. But then you compare the Dutch cuisine to the Swiss cuisine. And discover that cheese is a major ingredient there too. So you learn that specific types of cheese are hallmarks for respectively the Dutch and Swiss cuisines. And the more cuisines you compare it to, the more detailed hallmarks you will find. Comparing proteome maps of many different diseases works the same way.”

An added benefit of this approach is that for these other diseases it is often known what proteomes correspond with specific signalling pathways. “So finding common proteomes, points to similarities in underlying mechanisms.”

Major progress

These are promising steps. But when can patients expect treatments to arrive? “It is very hard to give an estimate,” Eickelberg admits. “I do expect major scientific progress in the next five to ten years. History shows that if you put smart people together in a consortium, this often results in a sudden surge of knowledge. And sometimes even in a paradigm shift: a completely new view on the topic that opens doors to many new possibilities. The intensive and transparent way we work together in the Lung Regeneration Consortium maximizes the chance of this happening.”

Powerful motivator

Eickelberg realises the relatively slow progress of medical science is hard on patients in need. “Anyone who has been a patient some time in their life, has experienced how important it is to have someone help you. Even medical doctors experience this when they can’t offer real solutions to their patients. Personally I have witnessed it too, since severe lung disease is common in my family. For me, this need is a powerful motivator. I feel it is my duty to help patients as fast as possible.”

Text: Karin Postelmans