In break-through research, a Nature paper published recently, demonstrates that a subset of cells in the lungs of ex-smokers has a mutational profile similar to those found in cells from non-smokers. This research suggests that quitting smoking might be promising at any stage of life, because it may ultimately result in the partial replenishment of lung tissue.

Amongst all cancers, lung cancer is the number one killer. 80–90% of deaths due to lung cancer are caused by tobacco. It is well known that the carcinogens found in tobacco smoke promote lung cancer, by causing DNA damage leading to mutations But the consequences of smoking on healthy lung cells remains unknown.

Yoshida and colleagues (from University College London and University of Cambridge) sequenced whole genomes of 632 colonies derived from single bronchial epithelial cells across 16 subjects (3 children, 4 individuals who had never smoked (never-smokers), 6 ex-smokers and 3 current smokers).  The researchers dissociated cells from the lungs of these individuals and isolated a type of epithelial cell called a basal cell which has the ability to replicate. These single cells were then grown into colonies which allowed the researchers to identify the DNA sequence of the original cell. The researchers then investigated the frequency and properties of the mutations present, how they differed according to age and smoking habits, and how these mutations related to those found in a type of lung cancer called squamous-cell carcinoma. Smoking tobacco massively increased the number of mutations per cell, compared to age matched non- smokers.

A key and novel finding in this study was that the researchers found a distinct population of bronchial epithelial cells with a near-normal mutational profile in individuals with a history of smoking. In other words they identified cells which had the same mutational profile as age-matched never-smokers. These near normal cells had low proportions of signatures from tobacco carcinogens. To assess the history of mitotic activity the researchers also estimated the telomere lengths. In particular, the cells with a near-normal mutational burden in ex-smokers had considerably longer telomeres than did their more-mutated counterparts, suggesting that they might have undergone fewer cell divisions. Furthermore, these near normal cells occurred four times more frequently in ex-smokers compared to current smokers, suggesting cessation of smoking somehow creates a pool of these near normal cells.

The researchers found smoking also caused mutations in crucial genes including TP53 and NOTCH1 that are driver mutations in squamous-cell carcinomas. Driver mutations (a mutation that gives a selective advantage to a clone in its microenvironment, through either increasing its survival or reproduction) were more frequent in patients with a history of tobacco smoking. There were significantly more driver mutations in individuals with a smoking history and showed an increase of 2.1-fold in current smokers compared to never-smokers. As expected no candidate driver mutations were identified in cells from children.  4–14% of cells in adult never-smokers had drivers whereas in current smokers, at least 25% of cells carried at least one driver. Interestingly, a small fraction of cells in smokers had two or even three coding driver point mutations -as many as is seen in some lung cancers.

The discovery of these near normal cells in the lung tissue exposed to tobacco raises a couple of interesting questions. 1) How these cells in the ex-smokers have avoided the high rates of mutations that are exhibited by neighbouring cells, and b) why these cells expand after cessation of smoking. The researchers suggest that the longer telomeres in the near normal cells in the ex-smokers, have undergone fewer cell divisions, and therefore potentially represent recent descendants of quiescent stem cells which are protected from the mutations.  Another explanation is mitotic quiescence itself, as replication is required to convert adducted DNA bases to mutations.

According to the World Health Organization tobacco kills more than 8 million people annually. There is ample scientific evidence and epidemiological data indicating that the health benefits begin immediately after quitting smoking, accrue over time since cessation and are evident even after quitting late in life. What this Nature paper has brought to the table for the first time is that, the benefits of quitting smoking could be facilitated by potentially replenishing the bronchial epithelium with cells that are essentially unscathed by decades of sustained cigarette smoking. Further research could be directed towards understanding the mechanism of protection and replication of these near- normal cells and harnessing this ability to repair the damaged lung tissue.

Take Home: Although the day to quit smoking is today, it is never too late to quit smoking no matter the age. Cessation of smoking does not only slow the accumulation of further lung damage, but can also re-awaken cells that have not been damaged by previous exposure to the carcinogen.