Mike Magee MD
President’s College at the University of Hartford
May 15, 2026
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 the role of cells, the germ theory, vaccination, sanitation and more with the 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 vulnerable and 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 Landsteiner was a member of the fledgling American Association of Immunologists (AAI), and the second member of that association 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. This insight first was associated with failed attempts at tissue and organ transplant which early on were met with rejection. As HLA matching became routine, the problem with rejection lessened but never fully disappeared. Even with relatives as donors, no two HLA fingerprints were identical. But the addition of drugs that could suppress immune reactivity extended the life of donated organs.
A second challenge was growing understanding of a group of chronic diseases lumped together as auto-immune diseases. These included Multiple Sclerosis, Rheumatoid Arthritis, Lupus, and others. Long term treatments of these diseases, where the immune system misinterprets “self” as “non-self” and attacks, remains challenging. Finally, as the 21st century dawned, scientists began to challenge a century of dogma on “self and non-self”, and the clear distinction between innate and adaptive immunity.
Fundamental questions had arisen. How and why did the body tolerate the flourishing and cooperative microbiome organisms? Why do mothers not reject fetal cells that leak into maternal circulation during pregnancy? And how was it that exposure to a relatively benign virus, Epstein Barr Virus, seemed to predispose individuals to later development of Multiple Sclerosis. Was “molecular mimicry” at fault?
As the new century dawned, there was intense focus on evolution of the immune system in the developing fetus. During pregnancy the fetal immune system doesn’t need to function since development is occurring in a sterile environment provided by the mother. But studies have revealed that by 4 weeks of development there is clear evidence that fetal cells have leaks into the mother’s circulation and the mother “tolerates” them, that is to say she does not launch an attack on them as “foreign.” In reverse, by week 13, mother’s protein antibodies or immunoglobulins cross over the placenta and appear in the fetus continuously until birth.
At birth, the babies immune system is antigenically inexperienced. This implies great vulnerability to potential attack by microbes. But the risk is largely ameliorated in breast fed babies by the fact the mother’s milk is rich in immune factors and cells. One milliliter of mother’s first milk (colostrum) contains up to 3 million cells. The risk to child is not entirely erased, and studies have confirmed at least 2 months of accentuated vulnerability especially to streptococcus, staphylococcus, meningococcus, Haemophilus influenza, and pneumococcus.
The newborn child is not entirely powerless to protect herself at birth. Elements of an innate system, developed and genetically sustained over millennia of “survival of the fittest” have ensured certain defensive physical, chemical and cellular weapons, even at the moment of birth.
To begin with, the newborn possesses certain physical barriers to infection including a multi-layered envelop of skin, and strategic hair that capture and obstructed pathogenic organisms. In addition, chemical washes including mucous, tears and gastric acids dilute, destroy, and wash away many invaders. Finally, a group of WBCs, notably those that are the direct descendants of granulocytic stem cells arrive on the scene soon after birth to challenge invading microbes that survive physical barriers.
Eighty percent of all cells in the body are blood cells, but almost all of these are Red Blood Cells (RBCs) whose primary function is to distribute iron bound oxygen throughout the body. But 1% of the blood cells, the WBCs, possess nuclei and have a very different function. They wage continuous war against harmful invading micro-organisms. Those available initially are descendants of the granulocyte stem cell line. These include neutrophils and monocytes which engulf, digest, and discard bacteria and some viruses, basophils that attack parasites, and eosinophils that are stimulated to action by allergens. Of these early responders, the most numerous, accounting for 60% of all WBCs, are the neutrophils. The fifth major type of WBC, arising from a different stem cell line, and accounting for 15% of all WBCs are the lymphocytes. They are much slower to arrive on the scene, but as we will see, tend to “hold a grudge” and remember prior offenders and respond aggressively on second challenge.
When doctors order a Complete Blood Count or CBC, the results include numbers and qualities of RBCs, and numbers of specific WBCs with breakout of these five types of cells. High levels of WBCs are often a reflection of active infection. Most commonly, the numbers of neutrophils and monocytes will be most prevalent in the initial response to standard infections. They surge toward the offenders, surrounding them and bathing them in highly destructive enzymes called “cytokines” that digest proteins. The bleach like washing kills and begins to dissolve the organisms, and the remains are then engulfed and digested in a process called “phagocytosis.”
In a standard skin surface bacterial infection, the site of this combat appears inflamed and abscesses, or collections of pus, may appear beneath the skin and require drainage. These white creamy collections are actually collections of organisms and attacking WBCs that have been bleached to death and sacrificed for the good of the whole.
If this sounds overly dramatic, it is useful to remember that micro-organism invaders have a distinct advantage over their human hosts. As experts remind us, “Infections reproduce much more rapidly than their hosts and can change their appearance to allow them to evade recognition. An effective immune system must cope with this unpredictability.”
Invaders have the capacity to penetrate various cells by evolving different pathways, and mimicking normal functions. They evolve continuously. And while bacteria tend to segregate together as free standing organisms, viruses hide inside the cell and must commandeer cellular equipment since they are ill-equipped to survive and reproduce on their own. A virus hiding inside a cell presents a special challenge when it comes to detection and eradication.
So humans have a granulocyte line of “first responders,” an Innate Immune System largely “hard-wired” into human evolutionary genomes, and a secondary response system, called to action when the first defense is not fully successful. It is powered by lymphocytes, slower to initially react, but with memory of prior offenses, and progressively more deadly to organisms which return to the scene at later dates. This capacity to remember powers the effectiveness of vaccines, which are simply an immune system reaction to purposeful exposure to a microbe or portion of microbe stripped of its deadly capacity but still identifiable and capable of triggering a lasting and protective immune memory response.
There are two main types of lymphocytes. The first is the “B-lymphocyte.” The B stands for bone marrow, the site where these cells originate. The second is the “T-lymphocyte.” It too develops initially in the bone marrow but rapidly migrates to the Thymus gland where it nests, matures, and awaits further instructions. The two cells work in unison but have different functions.
The capacity of lymphocytes to remember and respond relies on a system of “constant surveillance.” Each human posses an entirely unique set of Human Lymphocyte Antigens (or HLA’s) that attach to the surface of every one of our nucleated cells. One of the major functions of B-lymphocytes is to produce and secrete HLA-sensing receptors into the general circulation. These are called antibodies or immunoglobulins. They are “Y-shaped” proteins constructed of 2 light chain proteins and 2 heavy chain proteins. Each functions as a circulating antenna, surveilling, checking and double checking that every cell belongs to you. If the answer is yes, all well and good. No action is required. But if the answer is no, an immediate response occurs.
The detection system of the circulating Y-antibody uses the “V” top of the “Y” to detect and bind to circulating foreign proteins. Each invader is also distinct chemically. An antibody or immunoglobulin not only can detect a microbe cell that is not your’s, but also what that organism is. A protein of a measles virus, is different than a rabies virus. An e-coli bacteria is not to be confused with a spirochete. With a huge volume of constantly circulating antibodies providing this very active form of monitoring and a stringent exacting verification process, everything not human is identified as a threat.
Once the invader is marked as a threat, the standing column end of the “Y” attracts helper T- lymphocytes. A signal from the T-cell labels the invader for destruction and calls in B-cells that “recognize” the specific invader. With “specify” established, the B-lymphocyte makes millions of clones of itself to join the attack and also neutralizes any harmful toxins released into the circulation by the invader.
How exactly does the body remember? First. the millions of B-lymphocytes produce Y-shaped antibodies (or immunoglobulins – Ig) traveling in the blood. They are able to go anywhere blood goes, and are distributed evenly throughout the body. Invaders are identified with specificity and helper T-lymphocytes (stimulating highly specific B-lymphocyte clones) are called to the site. When the job is done, Killer-T cells will continue to reside in the tissue around the former site of action, alert but not activated, ready to attack if reinfected. This offers future protection, and in effect, survival. Only those with the right genes and effective B and T-cell responses will survive. Thus the genomic capacity becomes embedded in “the tree of life” no longer adaptive but now innate. What hasn’t killed you has made you (and your descendants) stronger.
Viruses offer a unique challenge because they imbed themselves inside healthy cells, and (if allowed) commandeer the cell’s control center to direct the cell to construct more viruses like themselves. The cell becomes in effect “a factory for the production of progeny viral microbes” hidden within the host’s own “healthy” cell.
Your specific HLA molecules are produced according to instructions from your genes – specifically a small focus of genes on the short arm arm of chromosome #6. The HLA’s special talent is to chop up bits of natural and foreign proteins inside your cells, and then transport those chemical segments to the cell surface where they are ‘displayed” and surveilled by B and T cells, and circulating antibody immunoglobulins. Foreign proteins trigger an attack. Natural proteins are “tolerated.” It is up to your HLA receptors and responding T-cells simultaneously to recognize the “self-component” and the foreign structure. Infected or cancer cells are sacrificed in order to destroy the embedded virus or halt the growth of a cancer.
As is now clearly evident, the immune response system is enormously complex and purposefully redundant since so much is at stake. Beyond the constantly evolving tools of the innate system (including liquid, chemical and cellular barriers), a granulocytic and lymphocytic cell line, HLA antigens attached to every nucleated cell in the body, and HLA receptor sensors on millions of immunoglobulin antibodies, there is also a fail safe emergency response inflammatory cascade, the complement system, that can be triggered in an emergency.
With such an array of weapons, it is not surprising that regulatory controls over the system are essential to avoid inadvertent over-reaction and self-damage. This may occur acutely, as in the case of allergy induced anaphylactic shock, or be a chronic inflammatory event as in autoimmune diseases like Type 1 Diabetes, Multiple Sclerosis, Lupus or Rheumatoid Arthritis. What is increasingly obvious, but still not fully understood, are the workings of regulatory feedback loops that can slow down or cut off the system when necessary. Some of the pieces of this system – such as loops of internal communication between immunologic control centers and our central nervous system, are beginning to be revealed as a byproduct of investigations into the human biome and graft rejection following transplantation.
Vaccines clearly offer humans a “better option” by early training and avoidance of the necessity to “react” and sometimes “over-react” to a natural invader threat. But as we’ve seen in modern times with RFK Jr. instigation and amplification of vaccine safety skepticism, addressing our immune challenges with a broad public health response requires cooperation to reach “herd immunity” rates. And cooperation is not exactly the human species strong suit.
One need not go all the way back to Rameses V in 1070 BC to find evidence of deadly waves of epidemics. In his case, his mummy remains have preserved the scars of the “pox” mark on his face. As for the epidemics of smallpox, plague, yellow fever, and more recently HIV/AIDS, Covid, and others, we remain at risk today as a human population.
We’ve been aware of the mechanics and the science behind immunization for at least three centuries. Back in 1716, the British Ambassador to Istanbul, Edward Wortley Montagu, and his wife, Lady Mary Wortley Montagu, had a front row seat to a rampaging local epidemic of disfiguring and deadly smallpox in Turkey. Lady Mary was very tuned into the human crises, in part because of the vulnerability she felt for her two small children in residence. She was invited to witness a practice of local Turkish priests and healers called variolation. It involved collecting the pus from active smallpox lesions in living victims and then inoculation through a skin surface scratch healthy individuals with the infectious liquid. The result was a milder variation of the disease, but then lasting protection from reinfection at a later date.
Lady Montagu was an immediate convert and had her son treated in Turkey, and her younger daughter, Mary Alice, treated (with heavy publicity) in London by the Royal’s medical team. Both children did very well. But the practice failed to gain general acceptance.
Smallpox was a major issue as well for early settlers in America. 20 settlers on the Mayflower died from the disease in 1633. Previously unexposed native Americans were ravaged, and privileged colonial leaders were at risk as well. Ben Franklin knew about variolation for Smallpox but refused to allow his son to receive the procedure. This lead to a lifelong regret when his 4-year old son succumbed to the disease in 1736.
At the time, Boston pastor and leader, Cotton Mather, learned about the procedure from Onesimus, his enslaved West African slave. Mather ran an experiment that demonstrated a drop in death rates with variolation from 14% to 2%. When he tried to mandate that all Boston citizens receive the treatment however, a mob attacked his home, throwing a rock through the front window with a note attached that read “A pox to you.” Still, the practice eventually became more accepted, in part because General George Washington mandated that all his soldiers be vaccinated in 1777.
Two decades later, in 1796, English physician and farmer, Edward Jenner, proposed that “the body could be primed to resist specific pathogens.” Jenner had observed that a common barnyard disease called cowpox (Vaccinia), caused lesions strangely similar to smallpox in humans. He also observed that milk maids appeared to be somehow protected against smallpox. Jenner inoculated an 11 year old son of one of his milkmaids with pus from a cowpox pustule, and then showed that his subsequent exposure to smallpox led to “a mild exposure with robust long-lasting protection from a far more virulent challenge.”
A half century later Louis Pasteur confirmed that germs caused diseases and that the body needed a strong defense. He developed a partially heat attenuated whole cell vaccine for Anthrax in cattle in 1877. In honor of Jenner’s work with Vaccinia Cowpox, be called his treatment a “vaccine.” He also developed (initially for wine sterilization) a protective heating procedure called pasteurization to destroy germs in beverages.
Diseases like Anthrax, Tetanus, and Diphtheria were infectious, but much of their deadly effect was the result of production and release of chemical toxins by the bacteria into the human blood stream. In fact, the most deadly childhood killer by far in NYC in 1900 was Diphtheria as a result of its toxin which triggered massive tissue swelling in the throat and subsequent suffocation of the child. The disease was being spread in infected milk. The public health response that halted the childhood epidemic was three-fold. First, local leaders, notably Dr. Abraham Jacobi and financier Nathan Straus established safe milk depots across the city, distributing pasteurized milk (146 degrees for 30 minutes) which immediately cut the infection rate by 70%.
The second breakthrough came from the American Association of Immunologists first ever Nobel Prize winner, Emil von Behring. This German physiologist discovered and created a life-saving Diphtheria antitoxin for children in critical condition. The serum was stimulated by infecting horses, and after a short delay, collecting blood and purifying the serum they had developed in response to exposure to the toxin. It had the power, when introduced to the young patients, of neutralizing the deadly effects of the Diphtheria vaccine.
The third breakthrough did not come from a physician or a scientist, but from Supreme Court Justice John Marshall Harlan on February 20, 1905. In a 7 to 2 Majority Opinion (Jacobson v. Massachusetts) . As the case affirmed, “Jacobson v. Massachusetts, 197 U.S. 11 (1905), is a landmark U.S. Supreme Court case in which the Court upheld a Massachusetts law requiring residents to be vaccinated against smallpox, affirming the state’s authority to exercise its police power to protect public health and safety.”
Thus, the state could insist on vaccinating a large enough portion of the population leaving infectious agents no place to spread. This was titled “herd immunity.” As we have recently witnessed however, when it comes to public health, progress is often imperfect and not permanent. One need only look at the Measles epidemics that has taken off in the U.S. in 2025 and 2026 as a result of misinformation and misguided leadership by vaccine skeptic and HHS leader RFK Jr. The numbers tell the story. In pockets of resistance to childhood vaccines, we have lost the advantage of herd immunity which prevented natural spread of the measles virus. This is especially relevant for this virus because it spreads very easily. Each actively infected person on average spreads the disease to 16 others. The only saving grace is compared to a disease like the Plague, with a kill rate of 60%, Measles virulence only leads to health in 1.3% of those infected.
When it comes to the battle between germs and the human immunological defense system, ecologists remind us that “The main problem that a parasitic species has to solve, if it is to survive, is to manage the transfer of its offspring from one individual host to another.” Tipping the odds in our favor, as we learned with the Covid pandemic prior to the creation of a vaccine, required denying access through testing, masking, and distancing.
The nation had had to wait for a vaccine earlier in its history. Yellow Fever outbreaks had been common across our nation for over a century before a Cuban physician, Carlos Finlay MD, in 1879, pointed a finger at the mosquito as the carrying agent for the causative Flavivirus. But a vaccine for the disease was still a half century away, arriving only in 1937. Aided by a massive period of science discovery in support of the US World War II effort, many vaccines became routine scheduled events across the nation, culminating in the monumental discovery of two polio vaccines in the 1950’s.
This was arguably an era of scientific over-exuberance. Consider the words of General George Marshall in 1948: “We now have the means to eradicate infectious disease.” Seven years later, Rockefeller Foundation scientist Paul Russell, published “Mastery of Malaria”, recommending a global DDT spraying campaign – which Rachel Carson successfully opposed. And eight years after that, in 1963 Johns Hopkins scientist, Aidan Cockburn, published “The Evolution and Eradication of Infectious Diseases” writing, “With science progressing so rapidly, such an endpoint (of infectious diseases) is almost inevitable.” Then Surgeon General William H. Stewart, agreed declaring with complete confidence that it was time to “close the book on infectious diseases.”
But on June 5, 1981, US scientific hubris evaporated. That was the day that the CDC published a brief notice in its weekly Morbidity and Mortality Review that announced a pending pneumonia causing viral epidemic for which there remains no cure till this day.
It read, “Pneumocystis pneumonia in the United States is almost exclusively limited to severely immuno-suppressed patients. The occurrence of Pneumocystosis in these 5 previously healthy individuals without a clinically apparent underlying immunodeficiency is unusual. The fact that these patients were all homosexuals suggests an association between some aspect of a homosexual lifestyle or disease acquired through sexual contact and Pneumocystis pneumonia in this population.”
With the aid of anti-retroviral drugs, HIV/AIDS has become largely a controllable chronic disease. A recent 2026 study has also revealed that individuals with certain HLA cellular markers that efficiently display segments of the HIV virus for recognition by killer T-lymphocytes had improved survival. This advantage was passed on to their subsequent children who inherited these HLA’s as part of the parent’s genome instruction booklet.
In any case, by 1992 a humbled Institute of Medicine reminded Public Health Officials that infectious diseases remained a threat stating “…they outnumber us by a billion fold, and mutate a billion times more quickly.” Four years later, epidemiologist Michael Osterholm MD drove the point home in testimony to Congress, “I am here to bring you the sobering and unfortunate news that our ability to detect and monitor infectious disease threats to health in this country is in serious jeopardy…For 12 of the States or territories, there is no one who is responsible for food or water-borne surveillance. You could sink the Titanic in their back yard and they would not know they had water.”
That same year Nobel Prize scientist Joshua Lederberg MD drove home the point writing, “Our fight with microbes is far from over…odds are tipped in their favor…pitted against microbial genes, we humans mainly have our wits.” Two decades later, Covid and defective national leadership contributed to the deaths of 1.3 million Americans, and over 7 million worldwide from a novel new virus for which human populations lacked immunity.
As bad as Covid was, it could have been a great deal worse. The new mRNA vaccines supplied by Moderna and Pfizer were literally life savers. The first Covid-19 vaccine was constructed and released in just 11 months. Prior to this, the fastest a vaccine was ever developed for use was the Mumps vaccine licensed in 1967 after 4 years in development. Before that, the standard development time was 10 to 15 years. Experts are quick to remind that speed didn’t compromise safety. “It was the result of decades of groundwork, massive funding, and a redesigned development process that ran multiple steps in parallel instead of one at a time.”
The timeline was tight but transparent. The full genetic sequence of the coronavirus was released by the Chinese government on January 10, 2020. That was “the starting gun” for development. Moderna had been working with a similar virus and testing a new approach using messenger RNA (mRNA). This allowed them to bring forward a candidate for testing in just 63 days. The human trial began in Seattle in mid-March, 2020. Following a similar path, Pfizer’s candidate went to trial in April, 2020. The first emergency authorization was approved on December 11, 2020.
The speed of these actions was the result of three contributing factors:
- Prior Research: Research into mRNA methodology dates back to 1960. By 2005, scientists had refined the chemistry and demonstrated it could safely trigger immune reaction without unintentional dangerous over-stimulation and allergic reaction. Within a decade, these same scientists demonstrated that the mRNA could be wrapped in lipid nanoparticles and safely delivered inside the cell intact.
- Parallel Processing: Collaborative studies between Moderna and NIH scientists into an mRNA vaccine had been ongoing since 2016. During this period, they had isolated the “spike protein” which would ultimately be created by the cell, and displayed by HLA particles on the cell surface to trigger an immune response. When the Chinese released the genome, they were able to simply “drop in” that spike protein code.
- Government Funding: The US government eliminated financial risk for the companies by investing over $29 billion in advance purchase commitments for 2 billion doses of the yet to be produced vaccine. The companies were able to build the doses while the product was still under testing. Once approved, doses were there already, ready to ship.
As we’ve seen, vaccines have been used since 1796 in animals and humans. The first type of vaccines used were “attenuated viruses” – treated so that they (almost always in weakened form) lost their ability to replicate. Today, rather than serial passage in live animals, vaccines for flu, polio, rubella and others are passed through tissue cultures or animal embryos to trigger a range of mutations that ultimately render the virus harmless. Despite their general safety, their live nature initially meant that there was a small chance that in the patient they might spring to life and cause disease. For this reason, inactivated vaccines were developed. This meant altering the genetic instructions with chemicals so that the virus would with certainty be unable to replicate. Their duration of protection however tended to be more limited, requiring boosters to preserve adequate levels of immunity.
mRNA vaccines were first examined as an alternative in 1989. mRNA were relatively simple and less expensive to develop and test. Experts recognized their potential use for “The speed of these actions was the result of three contributing factors: mRNA vaccines consist of single-stranded mRNA encoding the antigen of interest. They can be delivered as naked mRNA or enveloped in delivery systems to facilitate their internalization into cells. Once in the cytoplasm, mRNA is translated by the cell’s natural translation machinery into a protein… Upon its expression on the cell’s surface, it activates immunological responses and generates a protective immunity.”
The Covid vaccine program was a unqualified success and saved millions of lives. It proved safe and highly effective. The vaccine inserted molecular instructions through injection which would its way, transported with the help of lipid molecules into patients cells. It instructed the intracellular protein machinery to construct the covid-19 spike protein and facilitated its HLA transport to the cell surface where helper T lymphocytes detected its’ foreign nature. The helper T cells called in B-lymphocytes that cloned themselves and unleashed an antibiotic onslaught on circulating virus particles. The helper T-cells also called in killer T-cell that targeted and destroyed existing cells that were already harboring the covid-19 virus deep in their cytoplasm. The B and T cells “remembered” the virus, and that memory was reinforced with timely booster shots.
We’ve come to the end of our time. A three session course will allow us to pick up more detail at the President’s College University of Hartford campus in November 2026. But before we end this session, we must introduce the AAI’s 28th recipient of a Nobel Prize, 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. Specifically, she described and defined the role of one more type of T-lymphocyte – the T-regulatory cell or “Tregs.”
These are a missing link that may open a range of new insights in the area of immunotolerance and treatments for everything from autoimmune diseases, aging and cancer. As experts explain, “Regulatory T cells modulate the immune system, maintaining its homeostasis, tolerance to autoantigens, and limiting exaggerated responses. Deficiencies in their development or function are associated with inflammatory disorders and autoimmune diseases, while overactive cell function contributes to the suppression of tumor immunity and may impact host defense in infectious diseases. They are therefore attractive therapeutic targets in these areas.”
The list of areas we have not had time to cover is extensive and includes HIV’s ability to evade a cure, the role of Ebstein Barr Virus in the development of Multiple Sclerosis, immunotherapy breakthroughs in the treatment of melanoma, transplant rejection progress, immunosenescense with aging, and much more.
But we have laid out the basics of a remarkably complex and amazing story – The Birth of Immunology. Until next time, thank you.
