Mareike Lehmann enters the room, “Gen Laboratorium S1” is written on the door. On the wall next to it is a sign: “Caution! Biohazard – No unauthorized entry”. She puts on her smock, then a mask, and finally her hands slip into blue nitrile gloves. “We try to get as many samples of human lung tissue as possible,” says Lehmann, while approaching a young woman who is already sitting at the laboratory table at the Institute for Lung Health and Immunity (LHI) at the Helmholtz Zentrum München. “But we don’t get that every day, so we always have to be very spontaneous.” Lehmann looks over the shoulder of her doctoral student Maria Camila Melo-Narvaez. In front of the two women is a piece of lung in a pink liquid in a small plastic bowl. The team is researching a rare lung disease called idiopathic pulmonary fibrosis, or IPF for short. The tissue sample, about the size of a dice, should help the two.
Pulmonary fibrosis is a pathological change in the lung tissue with scarring. There are many subtypes of the disease, but probably the most common is idiopathic – pulmonary fibrosis for which no cause can be found. It mostly affects people over the age of 65. “The suffering of those affected is extreme,” says Lehmann. The fibrotic tissue crowds out the normal tissue and gas exchange is no longer possible – the patient dies. “The median life expectancy after diagnosis is three to five years. That’s much less than for many types of cancer.” Lehmann also deals with the disease privately. Her grandfather died from it and her aunt also got pulmonary fibrosis. “It seems that we have a family history,” she says.
The exact number of people suffering from pulmonary fibrosis is unclear. According to older data from the USA 68 out of 100,000 women and 89 out of 100,000 men are affected. Converted to Germany, estimates assume around 100,000 people with pulmonary fibrosis, as of 2018. There are probably more now. Not only because the population is aging, but also because of Covid-19. “It can be observed that more and more people have pulmonary fibrosis. It is, for example, a long-term consequence of Covid-19,” says Lehmann. “In this respect, we can expect the numbers to increase rapidly.”
For a long time, patients with idiopathic pulmonary fibrosis did not have the prospect of drug therapy, which has been shown to delay the disease. Until almost ten years ago, a lung transplant was the only way to gain at least a few years of life. However, the upper age limit for a transplant is usually 65 years, and in most cases there is no suitable donor lung.
However, since 2011 and 2015 there have been two approved drugs: Esbriet with the active ingredient pirfenidone and Ofev with the active ingredient nintedanib. However, both drugs have many side effects. “There are currently no means that can stop or even cure the disease,” says Lehmann. “There is a major medical gap that will keep us very busy in the future with regard to Covid-19.”
Lehmann investigates how lung cells age and she deals with the end of life of aging cells, senescence. Senescent cells can no longer perform their function. “But it’s not as if they just sit there and do nothing, but they are actually harmful, also for the cells around them,” says Lehmann. “Like a zombie who doesn’t really know what to do and just runs around wildly.” Since 2017, Lehmann and other researchers have been trying to therapeutically attack senescent cells and develop drugs that are effective against them – so-called senolytics, i.e. active ingredients that dissolve senescent cells. “They affect a biochemical signaling pathway in the cell, causing it to commit suicide,” says Lehmann.
Ultimately, her working group was able to show in animal experiments and cell experiments that senolytics both cause the senescent cells to die and reduce the fibrosis markers, which are chemical-clinical parameters that measure the extent of fibrosis. Thus, in animals, fibrosis partially regressed and cell layers recovered somewhat.
A kind of early warning system should improve the treatment
In the lab, Lehmann and Melo-Narvaez look at the piece of lung tissue in the Petri dish. Using tweezers, Melo-Narvaez takes the piece of tissue out of the shell, places it in a holder and uses a vibrating microtome to cut wafer-thin slices, each 500 micrometers thick, half a millimeter.
These discs will be irradiated with X-rays over the next few days. This in turn causes DNA damage, artificially aging the lungs by several decades. “In the next seven days, we’ll look at aging at top speed. Nobody has done that before,” says Lehmann. “And that’s how we induce senescence.” In this way, Lehmann’s group created an experimental setup with which they can try out new senolytics.
At the end of the year, Lehmann takes on a professorship in translational inflammation research at the University of Marburg. There she continues her research on the role of lung aging to pursue further questions. She is pursuing two goals: on the one hand, she wants to develop a kind of early warning system so that doctors can diagnose the condition at an early stage, for example using a blood sample. On the other hand, it is important to her that the results of the blood test can be followed by suitable therapy options. She wants to develop drugs that suppress or even reverse the aging mechanisms of idiopathic pulmonary fibrosis. “That’s the big dream.”