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For decades, most doctors ignored a mysterious two-lobed organ located behind the breastbone: the thymus, which was considered a largely useless mass for most of human life.
The ancient Greeks believed that this tissue knob might be the seat of the soul. In the early 1960s, a Nobel Prize winner dismissed it as a cell graveyard, “an evolutionary accident of little significance.” Today, scientists know that the thymus plays a crucial role in establishing a functional immune system during childhood, but then begins to rapidly shrink and become obsolete during adolescence.
Now, a wealth of research is reshaping the thymus from a minor player to a potent regulator of aging and immune health across the lifespan.
Research highlights the key role it may play in longevity and the prevention of cancer, autoimmune disease and cardiovascular risk. The work sparked interest in finding ways to rejuvenate the thymus, slow its decay and better understand its function.
“There was total expectation that the thymus would become irrelevant,” said Hugo Aerts, director of the Artificial Intelligence in Medicine program at Massachusetts General Hospital. In research published in the journal Nature, Eitz and colleagues found that people with healthier thymuses were less likely to develop lung cancer or die from heart disease or any cause. They also responded better to cancer immunotherapy.
The key question remains: Is the thymus a driver of these improvements in health outcomes or an indirect barometer of improvements in overall health? Why does its decline vary from person to person, and can it be slowed or stopped? Perhaps most fundamentally, why did it take so long to reconsider the thymus?
An accidental landmark study
The research that put the thymus in a new spotlight began by accident.
Kameron Kooshesh, a medical student in David Scadden’s laboratory at Massachusetts General Hospital and the Harvard Stem Cell Institute, is interested in understanding the role of the thymus in a small group of people: adults who have received bone marrow transplants. As these patients rebuild their immune defenses, researchers know the thymus plays the same role it did in childhood.
Then COVID shut everything down. The team turned to an experiment that could be conducted remotely, expanding the research question: What do the medical records of adults who had their thymuses surgically removed say about their overall health?
The findings shocked the team. People were more than twice as likely to die from any cause within five years after surgeons removed their thymus glands as similar people who had heart or chest surgery but still had heart or chest surgery. People without a thymus are twice as likely to develop cancer. When the researchers limited their analysis to people who had no immune-related problems before surgery, those who lacked the thymus were more likely to develop autoimmune diseases.
“Frankly, I thought it was more of a way to keep my students active during COVID, but didn’t think it was going to do much,” Skardon said. “We’ve all been hit. It’s had a big impact, not just on the things we were worried about … but on all-cause mortality.”
The findings were published in the New England Journal of Medicine in 2023 in an opinion piece called “Groundbreaking Research.”
organs of childhood
In the annals of human anatomy, the thymus has been a relatively unexplored territory for much of the history of medicine. Doctors often describe it as the last major organ whose function was discovered. It can be removed with a procedure called a “thymectomy,” which can be done for a variety of reasons, including to gain better access to the heart. As far as anyone knows, those guys are doing a great job.
“These are very subtle signals. It’s not like we take the heart out [and] The patient died,” Artz said.
It wasn’t until the 1960s that researchers began to piece together the key role the thymus plays in childhood.
The thymus trains immune cells called T cells (the “T” stands for thymus) to learn how to defend against viruses and other pathogens and how to avoid attacking healthy tissue. Children without transplants are born with severe immune problems and will die without a transplant.
T cells “come out of the bone marrow and go into this organ, and first of all, they have this school — I call it kindergarten or preschool. The cells start proliferating and expanding extensively,” said Andri Lemarquis, a physician and scientist working on restoring the thymus at City of Hope, a cancer research and treatment center. “Then they get deleted once they get to college. We don’t want any of them attacking our own bodies.”
The thymus is a key reason why our immune system doesn’t get out of control and attack our own cells, something immunologists call “self-tolerance.”
But during the teenage years, it begins to dissolve into fatty tissue. Many doctors consider it to be the organ that primarily degenerates during most of human life.
Rethinking and regenerating the thymus
New attention to the thymus is linking it to a wide range of health outcomes.
Aerts’ team addressed this problem by using artificial intelligence to look for patterns in large, long-term databases used to track cardiovascular disease and cancer. Thousands of people have had CT scans showing their thymus glands as part of health checks. His team used artificial intelligence to develop an overall thymus health score and then searched for patterns in these people’s health records over many years.
They found that a healthy thymus predicts good health based on a broad set of criteria. In one set of data, people with higher thymus health scores were less likely to die from any cause over the next 12 years. They are less likely to develop lung cancer or die from heart disease.
Interestingly, they also found that people with healthier thymuses were more likely to respond to cancer immunotherapy drugs, which trigger the immune system to fight cancer but do not work for many patients.
The new study cannot say that the thymus is responsible for the improved health outcomes, but it generates new clues to be explored.
For some, the new interest is long overdue.
“Finally, people realize that the thymus is an important organ!” said Paola Bonfanti, a cell biologist at the Francis Crick Institute and a professor at University College London, who has always been fascinated by the thymus paradox: The thymus has extraordinary regenerative capabilities, but it is also one of the fastest-aging organs.
“It contains the same stem cells that our skin produces, and we produce new skin every three weeks,” Bonfanti said.
Bonfanti is working on building a human thymus in the lab. In the long term, she hopes it will be possible to engineer thymuses from organ donors to help transplant recipients tolerate their new organs without taking harsh anti-rejection drugs. They protect the new organ from attack by the immune system, but come with many side effects.
She is also interested in exploring whether there are ways to slow down the natural degeneration of the thymus. This work could have many applications in autoimmune diseases, improving how people respond to vaccinations as they age, or improving how people respond to cancer immunotherapies.
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