The Oscars of Human Progress

For scientists, Nobel Prize week is our version of the Oscars; the most prestigious celebration of achievement across global disciplines. A measure of human progress. Announced every October by the Nobel Foundation in Sweden, the prizes honor excellence in physics, chemistry, physiology or medicine, literature, peace, and economics. They are the pinnacle of recognition in their respective fields, representing not just brilliance, but enduring impact; discoveries that have changed the way we understand and improve the world. 

History of the Nobel Prize

The prize is named after Alfred Nobel, who in his last will left the majority of his 31 million Swedish Kronor (SEK) fortune (now roughly 2.2 billion SEK, or ~234 million USD) to establish a foundation “for the greatest benefit of humankind.” Nobel envisioned a fund that would support discoveries advancing the human condition. The idea is that rather than celebrating an impressive career, we support discoveries that have pushed the progress of the human race as a whole. He also stipulated that the funds be invested in “safe securities,” with the generated interest used to finance the prizes. Today, the 2025 laureates will share 11 million SEK (~1.17 million USD) per award. 

The Nobel Foundation was established in 1900, and the first prizes were awarded in 1901; five years after Alfred’s death and following several legal battles over his will. Each of the six awards is governed by its own committee: five under Swedish institutions (the Royal Swedish Academy of Sciences, the Karolinska Institute, and the Swedish Academy), and the sixth, the Nobel Peace Prize, by a Norwegian committee. The reason for Nobel’s decision to entrust the Peace Prize to Norway remains unclear, though during his lifetime Sweden and Norway were united under a single crown. 

2025 Nobel Prize in Physiology or Medicine

As a biologist, I am naturally drawn to the Physiology or Medicine award. This year's laureates, Mary Brunkow, Fred Ramsdell, and Shimon Sakaguchi, were honored “for their discoveries concerning peripheral immune tolerance”. Their work fundamentally reshaped our understanding of how the immune system is regulated, and more importantly, how it avoids turning against itself. 

The reason this work is invaluable is because once we learned how the immune system generally functions, it is honestly a miracle that it doesn’t constantly self-destruct. 

Our immune system defends us against a relentless barrage of microbes through two layers of protection: the innate and the adaptive systems. The innate response is fast but non-specific, while the adaptive system takes longer to activate but has an extraordinary ability to remember previous encounters. That memory is what makes vaccines work: they train your adaptive immune system to recognize a pathogen without causing full-blown illness. This process is mediated by our T and B cells, which recognize foreign bodies (antigens). For more on how this has allowed us to better target vaccinations, check out a previous article I wrote about mRNA vaccines. 

Building Immune Memory

So how exactly does the immune system build memory? When your T and B cell receptors bind an antigen, they become activated and differentiate into two forms: effector cells, which fight infection, and memory cells, which persist for decades, ready to provide a faster and stronger response upon re-exposure. 

B cell receptors (BCRs) are called immunoglobulins (Ig). Some B cells keep them membrane-bound, while full-form B cells, called plasma cells, secrete them into the bloodstream as antibodies. Antibodies neutralize pathogens and mark them for destruction. 

T cell receptors (TCRs) are similar, but they never leave the cell surface. Unlike BCRs and antibodies, TCRs only recognize fragments of antigens displayed by antigen-presenting cells; cells that pick up antigen fragments from the infection site and run to show your T cells “fingerprints” of the enemy. The diversity of these receptors is immense, enough that virtually any molecular shape can be recognized. How this is achieved would take its own article but the staggering variability was first explained by Susuma Tonegawa, who received the 1987 Nobel Prize in Physiology or Medicine “for the discovery of the genetic principle for generation of antibody diversity”.

The Wild Part: How Does the Immune System Know “Self” from “Other”?

If our antibodies can recognize almost any structure, how does the body prevent them from attacking its own tissue?

That question led us to the study of immune tolerance, the mechanisms that prevent self-destruction. As it turns out, there are systems in place to ensure that “self-reactive” cells are eliminated before any damage can be done.

Early in their development, T cells (in the thymus) and B cells (in the bone marrow) undergo negative selection, a “self-test” in which cells that bind too strongly to self-antigens are destroyed or edited. This is called central tolerance. But this process is not perfect and some self-reactive cells escape, suggesting a need for backup regulation, known as peripheral immune tolerance. 

Researchers suspected that a subset of specialized “suppressive” T cells might patrol the body to keep self-reactive cells in check. In 1995, Shimon Sakaguchi provided definitive proof. He discovered that some T cells differentiate into a “regulatory” cell-type (Treg) that suppresses an autoimmune response. 

In biology, cell-types are usually defined by molecular markers on the cell surface. Pre-differentiated, or naïve, T cells contain a CD4 (CD = cluster of differentiation) marker. What Sakaguchi found was that Treg cells contain a CD4 marker as well as another marker, CD25. In the main experiment from his study (Figure 1), he found that mice that contained CD4 (CD4+) cells but were depleted of CD25 (CD25-) developed autoimmune characteristics, compared to CD4+/CD25+ mice.