“This is probably one of the most extraordinary papers on immunology I’ve ever seen,” said John Wherry, director of the Institute of Immunology at the University of Pennsylvania’s Perelman School of Medicine, who was not involved in the study. In the century. research. “It tells us that immunity can be extremely durable, if we understand how to make it properly.”
Andrew Soerens, a postdoctoral immunologist, successor to the project 21 immunizations, did not expect it to become his primary responsibility. “It looks like this might be the worst project ever, because it has no endpoint in mind. Or, it could have been pretty cool because it was fun biology,” he recalls.
This project is not something a researcher would write a funding proposal for. It was a discovery that threatened to overturn an entrenched idea—that T cells have an intrinsically limited ability to fight—with no guarantee of success. “It was almost an epic experiment in history to do. Nobody does an experiment that lasts 10 years,” Wherry said. “This is in contrast to funding mechanisms and five-year funding cycles—which really means every three years you have to do something new. It’s the opposite of how we train students and postdoctoral fellows, who usually stay in the lab for four or five years. It is in contrast to the short attention span of scientists and the scientific environment in which we live. So it really says something fundamental about really, really wanting to tackle a hugely important question.”
Indeed, the project remained unfunded for its first eight years, surviving solely on the lab members’ spare time. But its central question is ambitious: Do immune cells age? In 1961, microbiologist Leonard Hayflick Discuss that all of our cells (except eggs, sperm and cancer cells) can only divide a finite number of times. In the 1980s, researchers raise ideas that this can happen through the erosion of protective telomeres—a type of aglet at the end of chromosomes—that shorten as cells divide. After enough division, there are no more telomeres to protect the gene.
This project challenged Hayflick’s limits, and it quickly took up most of Soerens’ time: He raced down the flock of mice to vaccinate, sample, and start new armies of T-cells. He’ll count the cells and analyze the mix of proteins they make, noting what’s changed over the years. Such differences could indicate changes in a cell’s genetic expression—or even mutations in the gene sequence.
One day, a change was striking: high levels of a protein associated with cell death, known as PD1. That is usually a sign of cell exhaustion. But these cells are not exhausted. They continue to proliferate, fight bacterial infections, and form long-lived memory cells, all functions the lab considers to be markers of fitness and longevity. “I was a bit shocked,” Soerens said. “That was probably the first time I was really confident that this was anything else.”
So the lab kept going, and going. Ultimately, Masopust says, “the question is, how long is enough to sustain this before you make your point?” Ten years, or four lifetimes, feels right. “An extreme demonstration of nature is where it is good enough for me.” (For the record: All those cell groups are still going.)
