Your First Five Years Set Your Immune System Up for Life
The enlarged gland that set up a generation of discovery
The white mass in the upper front part of the chest, behind the breastbone and between the lungs, seemed to be the culprit. In the early 1900s, this gland, which was unexpectedly large in children who were operated on for heart abnormalities, seemed suspicious. Child cadavers are rarely autopsied and doctors had mostly come across this mass in adult cadavers, where it is much smaller. Assuming that its large size in sick children might somehow be contributing to disease, surgeons removed it. After the surgeries, though, those same children became very susceptible to severe infections and disease.
In the 1960s, Jacques Miller, a French-Australian research scientist working at the Zoological Society of London, was curious and asked a new question: what if that white mass played a role in our ability to fend off illness? To test this, he systematically removed that same gland from newborn mouse pups. He then observed their health, finding the answer he’d searched for: without this gland, the pups’ white blood cell count plummeted. Mouse pups who didn’t have that oddly large mass also lost the ability to fend off viruses and disease; their immune system had been incapacitated. The whitish organ, the white cells and the ability to resist infection were all linked. Interestingly, he also noted in subsequent papers a slight propensity for the thymus-free mice to succumb to cancers later in their lives.
Miller had discovered the function of what we now call the thymus gland; it produces T cells (Thymus cells) that we need for immune function throughout life. These cells are a large part of the reason your body can protect you against infection and illness. By around five years old, when your T cell count has been satisfied, your thymus begins to shrink, getting progressively smaller through adulthood. This organ wasn’t enlarged in kids because they were sick. It was larger in kids than adults because it needed to be—the gland’s large size had nothing to do with their cardiac illness.
Image source: Adalyn Kim, “The Lymphatic System: Structure, Function, and Key Organs” https://edubirdie.com/docs/glendale-community-college/bio160-introduction-to-human-anatomy-a/95530-lymphatic-system
Miller’s breakthrough set the stage for the science of T cell immunology. The T cells your thymus gland produced in your first years of life were the key to how we discovered a cure to certain cancers, among other diseases.
Unproven Field, Promising Results
In 1989 when I started my PhD, immunology was still barely considered a legitimate science. One early advisor in the molecular biology department even admonished me for choosing immunology to do my studies, since “it wasn’t a field.” Science has fads, things that are “hot,” which makes everything relevant seem important. When I was a PhD student, the trend in the biological sciences was to study the nature of genes, often using small unicellular organisms like bacteria and yeast. To my advisor at the time, immunology was a backwater pseudo-science characterized by funny and mysterious things like this white gland.
But also in that year, the HIV/AIDS epidemic was directing attention toward T cells as being pretty important for human health. We knew, even then, that HIV infects T cells, causing specific types called CD4 T cells, to plummet in number. Patients without these cells showed up in the hospital due to being severely immune-compromised, vulnerable to multitudes of infections and diseases that normal healthy people would easily fend off. AIDS showed that even soil bacteria can kill you when you don’t have your CD4 T cells. Anyone who needed a blood transfusion, ranging from hemophiliacs to car accident victims, and some childbearing mothers, could potentially be exposed to HIV. As a budding immunologist, that caught my attention. To my mind, that suggested the potential importance of immunology in addressing at least some diseases. When everyone else was studying gene regulation, immunology seemed like a place to make a mark.
But still, we knew very little back then; we knew that T cells were critical for immunity, and they had at least a few specific but poorly understood receptors on their surfaces. We diagrammed T cells as round balls with receptors sticking out, like sticks or strings extending from the cell’s surface. We were only aware of about ten molecules and signals on the surface of T cells. Any new one might do something incredibly cool and interesting. Or it might not do much at all. We didn’t yet have those answers.
Intrigued, I conducted experiment after experiment, initially to little effect. The molecule I was studying, CTLA-4, was predicted to be a protein receptor on the surface of T cells. It had been discovered in a French lab that had identified its DNA code. We knew it existed, but not much else. It might turn out to be fairly useless.
Still, I was curious enough about it to spend four years performing experiments that mostly produced incremental progress. Years later I’d understand that I’d had a very hard time studying it for those first years mostly because CTLA-4 has features we didn’t understand at the time that cause it to rapidly disappear from the surface of T cells. It is a molecule that routinely pops itself into the cell, shielding itself from being studied.
Then in 1994, I achieved a breakthrough in finally making a reagent that would bind to it. That reagent showed that the signals generated by CTLA-4 could be manipulated to boost or decelerate the immune system, like a brake pedal that we could press (to lower immune response) or release (to increase immune response). I soon began testing its efficacy on various diseases, including cancer. The protocol that resulted, known now as Checkpoint Blockade, became the poster child for immunotherapy of cancer. As I explained in this article, it was a new way to approach cancer that went beyond treatment, curing certain cancers altogether. It received FDA approval in 2011, exactly fifty years after Jacques Miller first published his findings about the thymus and T cells.
In 1961, Miller’s curiosity about children post-cardiac surgery didn’t just discover the function of a gland and its cells. Instead, it set the stage for an entire field of immunology. Since then, T cell immunology has paved the way for a growing number of scientific breakthroughs and the ability of those of us who followed him to ask the next curious questions, and the next and the next.