of medicine, but like all of human creation. Space travel is awesome. Agricultural revolution?

For the most part, pretty sweet. The entirety of YouTube? Up there, but maybe not as lifesaving as vaccination.

Vaccinations has its roots in variolation, a technique developed by Asian physicians

prior to the 1700s. They would take dust from someone’s smallpox scab and blow it

into their patient’s nose — the patient would experience a weaker version of smallpox,

but then they’d be immune to it for life. Variolation was far from perfect, and just sounds gross,

but when the alternative is contracting a potentially fatal version of smallpox, it

was a good first step. In the hundreds of years since, doctors have made huge advances

in vaccination technology like Edward Jenner’s famous smallpox vaccine made from cowpox virus,

or Louis Pasteur’s vaccines against rabies and anthrax. But here’s the thing — all

of these revolutionary concepts in science came before we knew how our immune system

worked on a cellular level. So today, we’re going to go through the story of early immunology

to learn how they figured out the cells of the immune system.

Around the same time as

Pasteur, a Russian researcher named Elie Metchnikoff was studying starfish larvae and noticed that

certain cells would engulf foreign objects. He called these cells phagocytes, which meant

devouring cells. This seemed like a viable explanation for how immunity worked — our

cellular defenses gobbled up potential threats. But during the development of the diphtheria

vaccine, another idea was put forward. German scientist Paul Ehrlich hypothesized that there

was some kind of anti-toxin floating in the blood that would confer immunity. These would

later become known as antibodies. So by the end of the 19th century, scientists knew that

germs caused disease, that substances in the blood could confer immunity, and that cells

could swallow up pathogens. But we still had some big questions to answer. Specifically,

there were two schools of thought regarding how immunity works. On one team were the “cellularists”

who thought that free floating phagocytes were more important to immunity than antibodies. This

became known as cellular immunity. On the other team were the “humoralists” who

believed in humoral immunity. To them, clearly something dissolved in the blood had to mediate

immunity. So to start with, your body has an immune system that keeps you safe from

pathogens, anything that causes disease like a bacteria, parasite, or virus. Those researchers

at the end of the nineteenth and start of the twentieth century were debating two types

of immunity that we now know are both present in our bodies. From 1900 to the 1940s, it

seemed like the humoralists had a better case. Experiment after experiment showed that antibodies

conferred immunity. Plus, scientists were zeroing in on how antigens hook up to antibodies

and antibodies’ structure. But the importance of the humoral theory was challenged during

a major experiment in 1942 by our old friend Karl Landsteiner, that dude that discovered

ABO blood types, and his colleague Merrill Chase. They took one set of guinea pigs and

gave them the tuberculosis bacteria, which meant they would build antibodies and thus

immunity to TB. Then they injected the blood serum with TB antibodies into naive guinea

pigs, or non-immunized guinea pigs, and later exposed them to the TB antigen. But the immunity

transfer didn’t work. So maybe antibodies weren’t the only thing conferring immunity?

Chase next tried to immunize his guinea pigs with a new solution, which accidentally contained

lymphocytes, white blood cells that play a huge role in our immunity. When the research

team looked under the microscope, they saw these immune cells at work, which strengthened

the cellular immunity theory. We had way more questions though. Like if there are millions

and millions of types of pathogens out there, how does our immune system make antibodies

for all of them? There was no way millions of species of cells were built into our bodies

for millions of antigens, so we must have to manufacture antibodies after being exposed

to the pathogen. This gave rise to something in the late 50s called clonal selection theory,

which, as the name suggests, implies clones, or copies of cells. First, humans along with

other animals have immune cells called lymphocytes. They’re a thing that exist and have a name

by this point. Lymphocytes respond to antigens according to receptors on the lymphocyte’s

surface. When that lymphocyte gets in contact with its appropriate antigen, it will proliferate,

or clone itself. From there, the clones will either secrete antibodies or recruit more

cells to respond to the pathogen. But that still didn’t show us how lymphocytes recognize

antigens themselves. Then in the early 1960s, scientists started paying more attention to

an organ called the thymus, an organ in the lymphatic system which until then, wasn’t

completely understood. So a scientist named Jacques Miller removed the thymus from infant

mice and noticed that the mice developed more severe infections and mounted weaker antibody

responses. So that seemed like some easy math. Take out the thymus and the immune system

weakens. But how exactly the thymus supported immunity was still a mystery. By this point,

scientists knew that cells in the bone marrow could make hematopoietic stem cells, those

types of cells that can become any type of blood cell. So maybe lymphocytes started in

bone marrow and mature in the thymus. Enter James Gowans, who traced lymphocytes all around

the body and found that they went from the blood into lymphatic circulation, then into

lymph nodes, and back into the bloodstream. This gave us the idea that the thymus manufactured

lymphocytes, which then traveled through circulation, eventually coming to secondary lymphoid organs

like lymph nodes. Now that we knew where lymphocytes came from, we could tie that back to the old

clonal selection theory. They got the idea that naive lymphocytes, or lymphocytes that

hadn’t been activated by an antigen yet, grew up in the thymus. Then

when they were excreted and made it to the lymph nodes, they would differentiate into

fully functioning, antibody-producing plasma cells depending on which antigen they encountered.

So they were born in the bone marrow but grew up in the thymus. These thymus derived cells

became known as T cells. Around the same time, separate scientists saw that lab chickens

developed an impaired antibody responsiveness when they removed their bursa of Fabricius,

a bird-specific lymphatic organ found near their little chicken butts. That complicated

our nice, tidy definition a bit because that meant that there might be two types of lymphocytes.

Through a series of experiments on chicken embryos, scientists found that different lineages

of lymphocytes developed in the thymus compared to the chicken’s bursa. These became known

as bursa derived cells, or B-cells, which mediated humoral immunity. Thus, the two superstar

cells of the adaptive immune system got their names. Fun fact, humans do have structures

called synovial bursa, but they’re more cushioning for our joints — so they’re

different from the bird version. That raises another question though. Humans aren’t birds.

Like not even a little bit. So we don’t have the organ that produces B cells that

birds do. So where do humans make B cells, and how does the whole immune response work

with all these moving pieces? As it turns out, B cells both form and mature in the bone

marrow itself. They only start to differentiate once an antigen hooks up to any of the receptors

on its surface. By now we’re in the 1970s, and we still had a few things to figure out,

like how the T cells don't just self destruct and kill our own cells. See, bacteria infect

our bodies differently than viruses. Bacteria will invade our bodies somehow, then reproduce

by splitting apart into two cells. But viruses get directly into the host’s living cells,

then use their host’s cellular machinery to reproduce, and eventually burst out of

those cells to infect more cells and keep the process going. So to keep that virus from

hijacking more of your cells, sometimes your immune system needs to kill off your own cells.

During an experiment published in 1974, researchers saw how our immune systems could differentiate

our infected cells from other cells. In it, they gave a virus to a bunch of lab mice,

and swapped T cells from one mouse to another. The T cells did their normal job as expected.

They’d destroy cells infected with viruses but, unexpectedly, only if the infected cell

came from the same strain of mice as the T cell. If a T cell detected that a random

cell was infected with a virus, but it was from some other mouse, it wouldn’t destroy

it. Basically, T cells showed that they would only help cells from their same family. This

would become known as self-nonself discrimination. This was a big development because it showed

that T cells only destroyed foreign cells if they presented an antigen and presented

a molecule that identified it as a “self” cell. That identifying molecule was major

histocompatibility complex, or MHC for short, a molecule that presents the antigen-of-interest

to different T cells. Then in 1978, scientists identified the dendritic cell, a phagocytic

cell that eats up pathogens and presents its antigen to the other cells, helping to eventually

grant immunity to that pathogen. That made it an APC, or antigen-presenting cell. I have

slayed this E coli for you! Behold! Feast thine eyes upon its carcass! One of the most

recent discoveries in the story of B and T cells shed some light on how these two types

of immune cells work together. In order for our cells to remember that pathogen, the APC

will present an antigen to one type of T cell so it can destroy the pathogen, while another

type of T cell will share that antigen with B cells, which then make antibodies for it.

That development would let us understand how those early vaccines at the start of the twentieth

century worked. The vaccine itself is a weakened or imitation pathogen that we administer to

people without immunity to that pathogen. Their bodies respond first by attacking the pathogen,

but then build up a reservoir of memory T cells and antibodies from B cells to attack

that pathogen in the future. After all those years of not knowing how vaccines were saving

lives, we finally learned how. Next time, we’ll learn about a major source of those

B and T cells, the lymphatic system. I hoped you liked this episode of Seeker Human, I

always love these history based episodes. They’re so fun to write. I’m Patrick Kelly

and thanks for watching.