A shortcut to reliable repair and growth of airway cells

Leading respiratory scientist Professor Sam Janes developed a rapid method to identify the needles in a haystack of drugs that stimulate growth of airway stem cells. 'This may lead to new treatments. But first we need to expand our work to more realistic models.'

In the Netherlands, about 600,000 people have COPD. According to the World Health Organization, lung damage from COPD is the third leading cause of death worldwide. “Considering the high morbidity compared to other diseases, respiratory disease is relatively underfunded,” says leading scientist prof. Sam Janes. “That is why I’m very happy with the Lung Regeneration Consortium and eager to contribute.” Janes works as a respiratory clinician, and is Head of the Respiratory Research Department at University College London (UK).

‘We need to know more’
Janes also works as a clinical physician and sees a lot of COPD patients. There are drugs available but a lot of patients don’t experience any relief, he notes. “The effect of the loss of lung capacity is very sad. Patients really need new therapies that make a difference.”

People with COPD have trouble breathing out, partly because their airways are narrowed. This is due to damaged and inflamed epithelial cells that line our windpipes. Basal cells are one of these epithelial cells and line the airways like a pavement. Some of them are also stem cells: these produce other types of cells that also make up the airways. Janes: “My research for the Consortium aims to find drugs that make the basal cells grow and control their stem cell behaviour. If we succeed, we can then work towards repairing the airways of patients.”

Skip years of research
Instead of developing new drugs, Janes decided to find out if there are existing drugs that stimulate basal cell growth. “Generally, after discovering a novel treatment it takes about 15 years to develop a drug that can be used in humans and get it approved for use in disease. We skip much of this time by turning the process around: we test drugs that are already proven to be safe.” For this his team combed through a database of FDA approved but unused medicines. These are drugs that for example have been tested for other diseases but proved not to work. They selected over a thousand types of drugs that might stimulate basal cell growth. “The aim was to experiment on a large scale: to test over a thousand types of drugs in one go on many different patients’ samples. Excitingly, we succeeded in creating such a High Throughput Assay.”

Promising drug candidates
From the haystack of drugs, Janes’ team identified twelve promising candidates for drug treatments: these proved to stimulate growth of human basal cells. But how did that work?

Janes’ lab receives biopsies from human airways, taken during procedures that patients undergo. After a sample arrives in the lab, it is broken up in single cells. These are put on a medium that specifically stimulates growth of basal cells and creates organoids: small versions of airway lining tissue. “When the organoids are big enough, a lab robot dispenses the cells evenly on a plate with 384 separate wells.”

Some cells multiply
Next, the robot dispenses the different drugs in each well. Over time some cells die, some stay the same and some will multiply compared to those in control wells. This way Janes identified the twelve promising drugs.

Nine out of twelve validated
“We are very grateful to the patients who consent to a biopsy,” Janes says. This way Janes can see if the drugs work in people of different sex, age and who use different drug prescriptions. Some twenty different samples are necessary to validate each of the twelve drugs. “So far, nine drugs have remained successful.”

Treatments for patients
Janes is hopeful that his research will lead to at least two types of treatments. One is to treat acute insults of the lungs, for instance caused by an inflammation or a burn. “We want to enable the basal cells to survive and grow in such a difficult situation, to enhance the recovery of the lungs.” A second treatment entails the transplantation of huge amounts of cells cultured in the lab. “Both have great potential to be put in use within the next 5 to 10 years.”

Next steps
So what happens soon? “Exiting things, actually.” Over the next two years Janes will expand his work to more complex models to find out what effect other cells have on basal cells. “After all, in the body the basal cells are surrounded by many types of cells. We will discover if the drugs still work or even work better with other cells present.”

Also, Janes wants to clarify how the drugs work. What signalling pathways of the cell do they effect? And which of those are particularly relevant for basal (stem) cell growth? “With this knowledge, we can check if there are other existing drugs known to influence these pathways. This can lead to rapid design of new treatments.”

Working together
Key to this progress is working in close collaboration with other lead scientists of the Lung Regeneration Consortium. Janes’ group cooperates with Melanie Könighoff (University of Pittsburgh, VS) because she developed the more complex model Janes needs to test his validated drugs in. And one of Janes’ scientist has worked in the lab of Carla Kim (Boston Childrens Hospital, US) to find out if the promising drugs also work in tissues specifically developed for transplantation.

Acceleration and fun
“Interacting with the most brilliant people in the field gives our work a great boost and makes it more robust. Different labs look at results from new angles. Working for the Consortium is also great fun.”

“The part of my work I love the most is training young scientists. Discussing with them brings fresh ideas to the projects: their minds are still open to creative sollutions that can overcome difficult challenges. Also, this also gives rise to an enthusiastic new generation of scientists to work towards more breakthroughs for future patients.”

LONGFONDS | Accelerate
In the international research program LONGFONDS | Accelerate, international top researchers are rapidly bringing solutions for chronic lung diseases closer. Under the direction of Longfonds, they work together intensively to achieve a medical breakthrough for asthma and COPD. Already this is yielding important insights and results.