The Birth of Immunology: Session I.
Mike Magee MD
President’s College at the University of Hartford
May 28, 2026
The Birth of Immunology is a story for the ages. In this 3 part series, we will travel from ancient civilization in pursuit of evolutionary context, explore two centuries of active scientific discovery, and embrace the challenges of new and emerging therapeutics that hold great promise for humans with auto-immune diseases, life threatening allergies, and cancer.
When English mathematician, and sometimes poet, Augustus De Morgan, put pen to paper in 1872, he was in a reflective mood. Having witnessed multiple waves of Plague and Yellow Fever, he expressed his humility in the face of forces he poorly understood. “Great fleas have little fleas upon their backs to bite ‘em, And little fleas have lesser fleas, and so ad infinitum.”
What he so nicely expressed was that life, and survival itself, involved a competition for resources, with winners and losers at every turn. And so it is here that we begin, around the time that scientists were describing the role of cells, the germ theory, vaccination, sanitation and more laying the ground work for a continuing story of the field of Immunology.
How should we describe Immunology? It is active, evolutionary, uniquely individualized, self-defining, defensive, targeted and systemic, deadly serious, corruptible, and complex. The story of Immunology is indeed a complicated narrative.
In the age of Augustus De Morgan, scientists were just beginning to appreciate the insights of ecology, that “All organisms are connected in a complex web of relationships. Although many of these are benign, not all are, and everything alive devotes significant resources to identifying and neutralizing threats from other species. From bacteria through to primates, the presence of some kind of effective immune system has gone hand in hand with evolutionary success.”
Immunology is about solving biologic problems on a grand and minute scale simultaneously. It applies equally to insects, microorganisms, and the wide range of creatures that play a role in disease transmission and multiplication. For these creatures, including ourselves, the goal is survival. Specifically for our species, slow and steady progress in public health and population safety have required recognition that we possess a highly connected web, on the surface and deeply embedded in our human chemistry, committed to achieving (as much as is humanly possible) a safe environment protected from harmful pathogens.
It is humbling to acknowledge how vulnerable we are. But throughout human history, we’ve been forced to admit the obvious – we are endangered by our own ignorance. That was the story that Leo Tolstoy relayed in his epic tale of Napoleon’s Russian Invasion in 1812. It was not Russian forces that brought him down, but other elements beyond his control. The weather of course, making worse the huge distances and beleaguered supply chain. But also microorganisms that his soldiers literally carried on their backs. He lost 1/3 of his army in its advance to Moscow due to Shigella dysentery, and lost the remaining 2/3 in his hasty retreat as a result of Typhus, caused by a bacteria, Rickettsia prowazekii, carried in the blood of body lice that had taken up residence in his soldiers filth-ridden clothing.
As Charles Darwin would describe later in the same century, all species are locked in a constant battle for resources. Winners survive. Losers do not. As we understand now, effective immune systems (codified in our genes) enhance survival, and weak immune systems do not.”
The second half of the 19th century was filled with scientific breakthroughs. Biologists embraced cell theory, that all life forms – plant and animals- were constructed of cells, and that cells replicated themselves. It took a bit longer to appreciate that microbes or germs that rely on humans for their nourishment and survival can only flourish if they are able to get close enough to cells without being repelled, and gain access to the chemical and biologic workings of the human organism.
As we will see, the human species has not stood idle but developed over time sophisticated strategies to identify and reject some of these invaders while tolerating others. How they do this involves mechanisms that differentiate between “self” and “non-self”, and consider friend vs. foe as well, a process that we still do not fully understand.
In broad terms, for much of the 20th century, we defined Immunology’s defensive system as a combination of an Innate System capable of immediate but non-specific assault on invading microorganisms and foreign bodies, and an Adaptive System, somewhat slower to act, but more powerful and targeted with a capacity to remember attackers should they reappear at a latter date.
Pathogenic microbes are dangerous opponents. They come equipped with an array of defensive systems and capacity for rapid replication, system wide dispersal, and toxin laden destructive weapons that can overwhelm a human host. Even when the human defenses respond, they must take care to not injure their own cells in the process, causing even more damage. To discriminate requires mechanisms that detect the structural features which are subtly distinct from human cells.
Traditional theory has held that the initial defenses against microbes are hard wired and encoded in our genes. This first set of responses constitutes the innate immune response. This capacity is largely “built in” to a large number of white blood cells (WBCs). They are poised to act rapidly as an initial host response. In contrast, the adaptive system involves different WBC’s and triggers a prolonged creation of molecules tailored to bond to specific invader’s surface proteins. These cells clone themselves when exposed to the same threat again, and can provide a stronger response without significant delay. Vaccines, as we will see, trigger this adaptive memory which is the basis for future immunity.
But we’re getting a bit ahead of our selves. let’s consider human cells by the numbers. A few questions and answers apply:
What is the average number of cells in an adult human? 36 trillion.
How many of those cells die and are replaced each day? 330 billion.
What percentage of the human body is composed of cells? 68%.
What percentage of a single cell is composed of water? 70%. We are largely fluid – 20% in interstitial fluid and lymph, 7,5% blood plasma, 7.5% fluid in bones, 7.5% in dense connective tissue, 2.5% in trans-cellular fluid.
How many times larger in volume is our largest cell versus our smallest? 10,000 times – human ovum versus human sperm.
What is the ratio of human cells to bacterial cells in the body? 1:1.
Understanding our cellular makeup is a fundamental step toward unraveling the mysteries of Immunology. It wasn’t until 1665 that Robert Hooke peered through his primitive microscope at a slice of cork and described little boxes he called ‘cellula’—resembling rooms that monks inhabited. 173 more years would pass before botanist Matthias Schleiden and zoologist Theodor Schwann, working together, proposed that a single cell is the basic unit of every organism, and that all organisms are made up of one or more cells.
They had also proposed that new cells arise spontaneously, but were wrong about that. Rudolph Virchow corrected them 17 years later with his theory “omnis cellular e cellular” stating every cell arises from a pre-existing cell. His work launched the field of cellular pathology and his description of the microscopic findings of cancer in leukemia. For the first time, he pointed science toward a future where disease might be diagnosed and treated based on cellular findings.
As important, Virchow pointed his contemporaries toward a cellular focus, including a study of blood. 80% (some 30 trillion) of all the cells in the body are blood cells. Only 1% of the cells viewed under the microscope were nucleated White Blood Cells or WBCs; and the remainder appeared vacant Red Blood Cells or RBCs without nuclei).
During the civil war and conflicts that followed, it became clear that transfusions of blood could be life saving. Direct human to human transfusion of blood in the battle field was attempted at the time. But problems with blood storage, clotting and deadly reactions at the time of transfusion limited the possible beneficial effects.
But in 1900, Austrian biologist, Karl Landsteiner, working with improved microscopes noted microscopic clumps on the surface of the red blood cells. Experimenting with different reagents, he was able to distinguish four different types of RBCs which he titled A, B, AB, and O. He also conducted human experiments proving that he could largely avoid deadly transfusion reaction by matching the blood type of donor and recipient.
In 1923, Landsteiner and his family emigrated to the U.S. where he joined the Rockefeller Institute in New York. Seven years later, in 1930 he received the Nobel Prize for his discovery 3 decades earlier. By then he had identified the “clumps” on the blood cell surfaces that he had first seen to be protein and carbohydrate antigens. In 1937, he added to his fame by identifying the “Rh factor” in blood, and the role that incompatibility between mother and fetus could play in “Blue Baby Syndrome.” Treatment with immunoglobulins would take three more decades to arrive in 1968, saving countless infants into the present.
Karl Landsteinerhas been heralded by the American Association of Immunologists (AAI), and the second immunologist to win a Nobel Prize. We’ll meet the first awardee a bit later. But as of 2025, 28 members of the AAI have won Nobel Prizes. Number 28 was Mary E. Brunkow. She is a molecular biologist and the Distinguished Investigator in the Hood Lab at the Institute for Systems Biology (ISB) in Seattle. Her Nobel acknowledged her role in defining the regulatory function of T-lymphocytes in adaptive immunity which we will discuss shortly.
But for the moment, focus on AAI awardee #16, French scientist Jean Dausset. His Noble Prize arrived in 1980. In mid-century, he had been exploring an unusual group of blood transfusion reactions in patients who’s RBC blood typing had been properly aligned. In exploring why the mismatch, Dausset uncovered a group of unique exclusive surface proteins on WBCs. These were later titled “Human Leukocyte Antigens” or HLAs.
Dausset was able to confirm that the incompatibility reactions he had witnessed were the result of a mismatch in White Blood Cell HLA’s. These were specific for each human individual, and uniquely different even in identical twins. As a measure of their specificity, they collectively became known as the HLA fingerprint.
Human Leukocyte Antigens (HLAs) – are found on the surface of nearly every nucleated cell on your body. HLA proteins are highly “polymorphic” with 28,000 different variable chains to mix and match.They are “the most genetically variable region in the human genome.” They are the essence of our individual identities.
As time went on, it became clear that HLA’s were the key to a surveillance system allowing the human organism to differentiate between “self” and “non-self” – the lifeblood of Immunology. No part of our body is cut off from its surveillance. For this reason, in aggregate, immunity consumes enormous resources, producing the large number of cells that it depends on for successful surveillance functioning.
As the new century approached, it became clear to scientists that turning off the immune system might be as important as turning it on. In Session II we’ll explore the range of molecular discoveries that begin to explain the critical role of immunology in modulating our human defenses against non-self organisms, but also the safeguards against over-reaction and tolerance of microorganisms that are essential and live in harmony with the human organism.
