The body’s most mysterious organ may play a key role in longevity and cancer
For decades, a mysterious, bilobed organ located behind the breastbone has been overlooked by most doctors and thought to be a largely useless lump for most of human life: the thymus.
The ancient Greeks suggested that this knob of tissue might be the center of the soul. In the early 1960s, a Nobel laureate dismissed it as a mere graveyard for cells, “an evolutionary accident of no great significance.” Today, scientists know that the thymus plays an important role in establishing a functioning immune system in childhood, but begins to wear out rapidly during adolescence.
Now, a body of research is transforming the thymus from a minor player into a powerful regulator of aging and immune health throughout life.
Studies highlight the important role it can play in longevity as well as protection against cancer, autoimmune diseases, and cardiovascular risk. The study sparked interest in finding ways to rejuvenate the thymus gland, slow its decay and better understand its function.
“It was assumed that the thymus would become completely irrelevant,” said Hugo Aerts, director of the Artificial Intelligence in Medicine Program at Mass General Brigham. In studies published in Nature, Aerts and colleagues found that people with a healthier thymus were less likely to get lung cancer or die from heart disease or any other cause. They also responded better to cancer immunotherapy treatments.
Key questions remain: Is the thymus the driver of these improved health outcomes, or an indirect barometer of better overall health? Why does its decline vary between different people and can it be slowed or stopped? And perhaps most importantly, why did it take so long for the thymus to be re-evaluated?
An accidental landmark study
The study that sheds new light on the thymus started by chance.
Kameron Kooshesh, a medical student in David Scadden’s laboratory at Massachusetts General Hospital and the Harvard Stem Cell Institute, was interested in understanding the role of the thymus in a narrow population: adults receiving bone marrow transplants. As these patients were rebuilding their immune defenses, researchers knew that the thymus played a role just as it did in childhood.
Then covid shut down everything. The team expanded on the research question by turning to a remote experiment: What did the medical records of adults who had their thymus surgically removed say about their overall health?
The findings stunned the team. In the five years after surgeons removed their thymus, people were twice as likely to die from any cause compared to a similar group of people who had had heart or chest surgery but still had the surgery. Those without a thymus were twice as likely to get cancer. When the researchers restricted the analysis to people who did not have immune-related problems before surgery, those lacking the thymus were more prone to autoimmune disease.
“Honestly I was thinking it was more of a way to keep my students active during covid and I didn’t think it would show much,” Scadden said. “We’re all affected. This has a huge impact not only on the issues we’re concerned about, but also on all-cause mortality.”
The results were published in the New England Journal of Medicine in 2023, along with a perspective article called “pioneering research.”
An organ of childhood
In the human anatomy record, the thymus was a relatively unexplored region for most of medical history. Doctors often describe it as the last major organ whose function was discovered. It can be removed through a procedure called a “thymectomy,” which can be done for a variety of reasons, including to provide better access to the heart. As far as anyone knows, these people did a good job.
“These are very subtle signals. It’s not like we’re removing the heart. [and] the patient dies,” Aerts said.
It wasn’t until the 1960s that researchers pieced together the important role the thymus plays in childhood.
The thymus trains immune cells called T cells (“T” stands for thymus) on how to defend against viruses and other pathogens and how to avoid attacking healthy tissues. Children born without this have serious immune problems and die without a transplant.
“T cells come out of the bone marrow, they settle inside this organ, and they first have this school — I call it nursery school or nursery school. The cells proliferate and expand rapidly,” said Andri Lemarquis, a physician and scientist who focuses on repairing the thymus at City of Hope, a cancer research and treatment center. “Then they come to college and get wiped out. We don’t want any of them attacking our own bodies.”
The thymus is a key reason why our immune systems don’t get out of control and attack our own cells; Immunologists call this “self-tolerance.”
However, in humans, it begins to turn into fat tissue during adolescence. Many doctors thought it was a largely vestigial organ for most of a human’s life.
Re-evaluation and renewal of the thymus
New interest in the thymus links it to a wide range of health outcomes.
Aerts’ team got to the problem by using artificial intelligence to find patterns in large, long-term databases used to track cardiovascular disease and cancer. As part of health studies, thousands of people have had CT scans that reveal their thymus. His team used artificial intelligence to develop an overall thymus health score and then looked for patterns in health records that followed these people over years.
They found that a healthy thymus predicted good health across a broad set of criteria. In one data set, people with higher thymic health scores were less likely to die from any cause in the next 12 years. They were less likely to get lung cancer or die from heart disease.
Surprisingly, 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 in many patients.
The new research cannot say that the thymus is the cause of better health outcomes, but it does create new clues to explore.
For some, the new attention is long overdue.
“Finally people realized that the thymus is an important organ!” Paola Bonfanti, a cell biologist at the Francis Crick Institute and professor at University College London, who is fascinated by the thymus paradox, said: The thymus has an extraordinary ability to regenerate, but it is also one of the fastest-aging organs.
“It contains stem cells equal to those in our skin, and we grow new skin every three weeks,” Bonfanti said.
Bonfanti is trying to create a human thymus in the laboratory. In the long term, he hopes it may be possible to grow a thymus from an organ donor, helping transplant recipients tolerate their new organs without taking harsh anti-rejection drugs. These protect the new organ from attack by the immune system but come with many side effects.
He is also interested in investigating whether there are ways to slow the natural deterioration of the thymus. This study may have many applications in autoimmune diseases; It could improve how people respond to vaccines as they get older, or improve how people respond to cancer immunotherapies.
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