The Lister Lecture: Regenerating the Lung

Joseph Lister Surgeon scientist Joseph Lister discovered the effectiveness of antisepsis in the 19th century. He based his work on the use of carbolic acid, a derivative of creosote, which was used to prevent the wood in railway ties from rotting. He used carbolic acid (phenol) to prevent infection in compound fractures and in abscesses. After confirming Semmelweis’s neglected discovery that surgeons can transmit infections from septic patients, Lister introduced the revolutionary concept of asepsis to the practice of surgery.

Tom Waddell began his Lister Prize lecture at Surgical Grand Rounds by showing us a lung transplant patient who was totally transformed from near lifelessness to athletic vigor by her treatment. The effectiveness was breathtaking. “The limit to this therapy is the severe shortage of donor organs and the fact that the treatment involves allogeneic tissues. Mechanical support using ECMO (extracorporeal membrane oxygenation) as an alternative has all of the limits that go with pumps.” Tom described the wide breadth of regenerative medicine approaches explored as alternative solutions in his lab.

Cell therapy can improve injured organs and enhances endogenous repair, but cannot replace function. Cell replacement with precursors requires removing endogenous stem cells and then putting in gene- corrected progenitors. That is regularly done for bone-marrow transplantation, as all the cells can be wiped out and the marrow repopulated. It is much more difficult in the lung. “Amy Wong in our lab discovered a unique population of bone marrow cells with a special propensity to populate the lung in mice. Sarah Gilpin studied sternal marrow in lung transplant recipients and found the same type of cells in humans. Administration of Clara Cell Secretory Protein (CCSP) positive stem cells via the airway

causes proliferation of the recipient’s cells, restoring the respiratory epithelium, and this may be useful in a variety of lung conditions. Using the combination of ablation of airway epithelium followed by transtracheal delivery of bone marrow cells, Pascal Duchesneau has achieved remarkable success in cystic fibrosis mice.”

An alternative approach to the shortage of donor organs is to grow them in the laboratory. For example, ongoing work in Tom’s lab is evaluating the role of decellularization and recellularization in the creation of new airways and lungs themselves. Tracheal replacement using decellularized tracheal allografts is a promising approach. “The decellularization techniques in current use tend to make the trachea floppy but Siba Haykal is evaluating various approaches to combat this challenge. The cells used to repopulate must be arrayed in order to move foreign material from the airway via the mucociliary carpet. John Soleas is using sophisticated bioengineering approaches such as nanotopography of the underlying substrate which may allow creation of this orderly orientation. Geff Frost has developed a device for decellularizing the entire lung by rotating it during perfusion to thoroughly distribute the decellularizing solution. The next step will be to recellularize the entire lung which will require massive numbers of epithelial and endothelial cells.

One such approach is to use partial reprogramming of lung cells towards induced Pluripotent Stem (iPS) cells. Stem cells retain their epigenetic memory of their tissue of origin. Lily Guo is working to determine if partial re-programming, for a short period of time will allow expansion of lung epithelial cells, which could then revert to lung epithelium upon withdrawal of the reprogramming stimuli.”

Tom concluded his lecture by acknowledging the incredible hard work of the many members of his lab, past and present. He also expressed his thanks to the other members of the Thoracic Division and the Department of Surgery for the support of this work.

M.M.