“It’s probably one of the most extraordinary papers in immunology that I’ve easily seen in the past decade,” said John Wherry, director of the Institute of Immunology at the University of Pennsylvania’s Perelman School of Medicine, who was not involved. at the study. “It tells us that immunity can be incredible sustainable, if we understand how to generate it properly.
Andreas Soerens, a postdoctoral immunologist who inherited the project 21 immunizations did not expect it to become his main responsibility. “It felt like it could be the worst project ever because it had no end point in mind. Or it could be kind of cool because it was interesting biology,” he recalls.
This project is not something a researcher would ever write a grant application for. It’s an exploration that threatens to bend a deeply held notion – that T cells have an intrinsically limited ability to fight – with no guarantee of success. “It’s almost a historically monumental experiment to do. Nobody does an experiment that lasts 10 years,” says Wherry. “It is at odds with funding mechanisms and a five-year funding cycle, which basically means you have to do something new every three years. It is at odds with the way we train our students and postdocs, who usually spend four or five years in a lab. It is at odds with the short attention spans of scientists and the scientific environment in which we live. So it really says something fundamental about really, really wanting to address a critically important question.”
Indeed, the project remained unfunded for its first eight years, surviving only on the lab members’ free time. But the central question was ambitious: should immune cells age? In 1961, microbiologist Leonard Hayflick argued that all our cells (except eggs, sperm and cancer) can only divide a finite number of times. In the eighties, researchers brought up the idea that this could be due to the erosion of protective telomeres – a kind of aglet at the end of chromosomes – that shorten as cells divide. After enough divisions, there is no telomere left to protect the genes.
This project challenged the Hayflick limit, and it soon dominated most of Soerens’ time: He would run to the mouse colony to immunize, sample, and start new cohorts of T-cell armies. He counted cells and dissected the mix of proteins they produced, noting what had changed over the years. Such differences may indicate changes in a cell’s genetic expression, or even mutations in the gene sequence.
One day, a change caught my eye: high levels of a protein associated with cell death called PD1. It is usually a sign of cell exhaustion. But these cells were not exhausted. They continued to multiply, fight off microbial infections and form long-lived memory cells, all functions the lab viewed as markers of fitness and longevity. “I was quite shocked,” says Soerens. “That was probably the first time I was actually quite sure that this was the case something.”
So the lab went on and on. Finally, says Masopust, “the question was, how long is long enough to keep this up before you make your point?” Ten years, or four lifetimes, felt good. “An extreme wildlife demonstration was where it was good enough for me.” (For the record, all those cell cohorts are still going on.)