“It’s a story that revolutionized science and medicine,” writes Dr. Sefik Alkan, a Turkish-born immunologist and historian. The discovery is now used in diagnosis and treatment of the pantheon of diseases “from rheumatoid arthritis to cancer.”
Now we’re getting close. The pieces are coming together, the exploration leading to application, to real-world solutions. None, arguably, was as significant as the discovery of the monoclonal antibody. This next scientific treasure likely will touch every reader at some point, if not directly, then through a family member. So it’s useful to grasp this piece to understand what might someday be injected into your body to extend or save your life.
The story starts like this: A Dane, an Argentinian Jew, and a German walk into a research lab . . .
The first of the three wise men was Niels Jerne, a Danish immunologist who was among the elite thinkers of his era and the founder of the Basel Institute for Immunology. “In his office,” Alkan writes, “there was a long table adorned by dozens of scientific journals; all were being read regardless of language (English, Dutch, Danish, French, and German).”
Jerne had created a way to isolate and count antibodies.
The discovery here is referred to as the Jerne plaque assay. From the University of Windsor website, I’ll draw the first few steps in what I think of as a kind of recipe—a dip of the toe into the complexity of immunology—and then I’ll just summarize the darn thing and its meaning.
You get the idea of its complexity (which eventually involved a centrifuge; more salt baths; mouse spleen cells, having been washed, put onto slides, sealed with paraffin wax, then incubated; and finally, the viewing of the results under a microscope).
What resulted was a plaque that, viewed under the microscope, would allow the counting of antibodies.
It was a huge step. Why? When you contract a virus, your body generates antibodies to fight it. Thanks partly to Jerne, doctors regularly use tests that isolate our antibodies as a way to understand the type of bug we’re fighting, how effectively we’re fighting it, and the intensity of the fight going on between our immune system and the pathogen.
Wise man number two was César Milstein, from Argentina. He had figured out an ingenious way to create lots of antibodies for purposes of studying them. His tactic for generating antibodies involved mating a B cell with a cancer cell. This worked wonders because cancer cells, for all their evils, have an important scientific value: Cancer cells grow and grow. They are the body’s weeds. What Milstein did by fusing a B cell with blood cancer, called myeloma, was to create a lineage of B cells with cancer’s powerful reproductive cycle. Now Milstein had a petri dish filled with antibodies, which allowed science to study and experiment with huge batches of these precious defenders.
In 1973, Milstein came to Basel to give a talk on this process, and listening there was scientist number three, Georges Köhler, the German.
Long (and complex) story short (and simple), Köhler combined the techniques of Jerne and Milstein. He used mice and sheep to isolate individual antibodies and then make countless copies of them.
For the first time, scientists could isolate a cell with a particular antibody and make endless copies of it. In turn, this technology allowed researchers to begin to make distinctions between and among lots of different cell types with antibodies. This was akin to creating the most powerful microscope that cell biologists had ever seen because it let them distinguish one cell type from another, determine which had what kinds of antibodies and also how many antibodies appeared on each different cell.
As a first basic step, this began to reveal that, for instance, B cells were far more varied than people originally thought. There were thousands of antibodies on the surfaces of B cells.
Once isolated, those antibodies could be used for study. For instance, if we knew what particular antibodies responded to particular pathogens, could we then figure out how the deadly diseases attacked or how the dance between self and alien took place?
Dr. Fauci told me the change led to a profound shift for immunology, turning practical a field that had been esoteric even as late as the 1970s and ’80s. “All of a sudden, the immune system was having an impact on more diseases than you could possibly imagine,” he said. He didn’t mean that the immune system was having a new effect, but rather that it was now clear to scientists how powerful the effect was everywhere. “Cancer, autoimmunity, auto-deficiency, allergy.”
These isolated and multiplied antibodies were known as monoclonal antibodies. They are changing your life, right now. Drugs built on monoclonal antibodies have become a dominant source of drugs in the early part of the twenty-first century. The annual market for these drugs is nearly $100 billion. They work by intensifying—or dulling, as the case may be—the performance of a particular antibody so that the body does a better job of attacking a life-threatening risk, like cancer, or, alternatively, dampening our elegant defenses so that the immune system doesn’t behave so aggressively and cause autoimmunity.
The drugs have names like Humira and Remicade (which Linda and Merredith both tried in an attempt to try to slow their zealous immune systems) or ipilimumab, which has saved countless cancer patients, or nivolumab, which saved Jason. In the upcoming stories, you’ll see the development and work of some of these miraculous medicines in an intimate way. In a general sense, the aim of these drugs is a relatively precise manipulation of the immune system, a molecular-level monkeying, rather than the scorched-earth tactic of previous drugs.
As a reminder, picture the difference between two cancer treatments, chemotherapy and immunotherapy. In traditional chemotherapy, toxins that destroyed fast-dividing cells got dumped into the body, ideally killing, say, a lung tumor, but taking out lots of healthy tissue as well. This was the proverbial war of attrition. The Festival of Life had to outlive the tumor and the treatment. With nivolumab or ipilimumab, as you’ll see, the idea is to use molecular tinkering to unleash the immune system to attack cancer—using the body’s natural defenses—rather than injecting bleach into the body and killing everything that moves.
This is complex stuff. Where are we in immunology’s story?
For most of human history, infection, even modest infection, killed people with the terrifying regularity of an open wound, the ingestion of undercooked meat, the casual exhale of flu inhaled by another, pneumonia passed from hand to hand and wiped on the nose. Then over the centuries, scientists took baby steps toward understanding these infections and dipped a toe into how our bodies fought back. These scientists came from all over the world, which is worth noting because it shows the powerful, essential value to our survival of cooperation across national boundaries and cultures.
We got a big break with vaccines and antibiotics. These helped keep us alive without our really understanding how the immune system worked. More or less blindly, we squirted medicines into our bodies; they sometimes worked and often didn’t, and we frequently didn’t know why, one way or the other. But we began to chip away at the details too, particularly in the middle of the nineteenth century.
The T cell came from the thymus and seemed to play a huge role in mounting a defense, but exactly how it did so wasn’t clear.
Ditto with the B cell, which came from the bone marrow, played a huge role, and seemed to have essential interaction with the T cell.
A Japanese scientist (Tonegawa), who studied in San Diego, then made a discovery in Switzerland that explained immunology’s big bang: Our DNA rearranges itself in utero and forms millions of antibodies capable of binding to—and attacking—a trillion different antigens.
An Australian vet (Doherty) worked with a transplanted Swiss scientist to figure out that the T cell distinguished alien from self.
Then came a Russian and a final major discovery that came surprisingly late in the story of our elegant defenses. There isn’t just one immune system, but two.