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Devastating disease of the lung is a new research gift’s focus

Medicine@Yale, 2018 - June July


The lungs are made up of some 30 to 40 different types of cells. “When you get sick, these cells can change. New cells can come in and resident cells can change over,” says Naftali Kaminski, MD, Boehringer Ingelheim Pharmaceuticals, Inc., Endowed Professor of Medicine (Pulmonary), and chief of the Section of Pulmonary, Critical Care, and Sleep Medicine (Yale PCCSM) at the School of Medicine. If researchers understood the interactions that take place between cells as disease takes hold in the lungs, he says, they might be able to develop targeted treatments to block crucial steps in the disease process.

A particular priority is idiopathic pulmonary fibrosis (IPF), a disorder where debilitating scarring develops on the lungs for unknown reasons. An estimated 132,000 to 200,000 Americans have IPF, and 50,000 new cases are diagnosed each year according to the Pulmonary Fibrosis Foundation. As many as 40,000 die from the disease every year.

Kaminski and his lab team are poised to take a major new step in IPF research, fueled by a gift of nearly $1 million from the venture philanthropy group Three Lakes Partners. The organization, whose mission is to accelerate progress in IPF research, was established by benefactor Thomas Hurvis, who lost his wife to IPF in 2015.

Using single-cell transcriptomics, Kaminski and his team plan to sequence the RNA (ribonucleic acid) of every cell in more than 100 donor lungs affected by IPF and other lung diseases. Ivan O. Rosas, MD, a physician at Brigham and Women’s Hospital in Boston and associate professor of pulmonary and critical care at Harvard Medical School, is providing the lungs for this research as part of an ongoing collaboration. RNA contains a transcript of the DNA sequence, and influences gene expression. Analysis of the entire transcriptome can reveal which genes are turned on at certain times and which are turned off.

With prior available resources, this painstaking research would have taken years. But with the infusion from Three Lakes, the timetable will be far shorter. “Within three or four months, we hope to have ‘The IPF Cell Atlas,’ which will identify how the cell populations of the lung change during fibrosis and scarring,” says Kaminski.

Kaminski, whose team led the field in applying high throughput genome scale transcript profiling to identify biomarkers and new drug targets using bulk tissue, anticipates that whole transcriptome single cell sequencing, to be performed at his section’s Center for Precision Pulmonary Medicine (P2MED), will dramatically alter the understanding and management of IPF. “We have biomarkers that are good enough to predict mortality in patients, but not good enough to tell which pathways we should intervene with in every patient.”

The new research, Kaminski says, would identify in detail all the aberrant pathways in every cell in the fibrotic lung, and could potentially lead to development of therapies to correct these pathways. It also could allow identification of biomarkers which would indicate what pathways are activated in each patient, leading to development of the sort of targeted individualized therapies that comprise the emerging field of precision medicine.

The onus to identify and develop applications for the research findings will not lie solely with the group at Yale. Kaminski’s team does not just aim to complete the sequencing as soon as possible; it also will share the results in short order. In a field that desperately needs to accelerate progress for patients’ sake, Kaminski bucks the notion that scientists ought to guard their data. In fact, a postbaccalaureate researcher in Kaminski’s lab, Taylor Adams, presented the team’s first single-cell data in a poster at last year’s Pulmonary Fibrosis Foundation Summit in Nashville. That presentation, Kaminski believes, first attracted Three Lakes’ attention.

Kaminski embraced the philosophy of sharing lab data nearly two decades ago when he trained under Dean Sheppard, MD, at the University of California, San Francisco. “I was worried about sharing data too early at some point,” Kaminski explains, “and [Sheppard] said, ‘You should be lucky [enough] to have data that someone else wants to steal from you.’ ”

The open approach aligns well with Three Lakes’ vision for the project, which is to open as many viable avenues toward new and effective treatments as possible, and to do so with the utmost speed.

“Good science has the tendency to lead to more questions,” says Ken Bahk, PhD, managing director of Three Lakes Partners. “This study should lead to so many new paths to investigate and ideally to a much better understanding of IPF and a more accurate and highly probable path to new therapeutics.”

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