Core Framework & Diagram How Were Antibodies Discovered?
July 24, 20261 Min Read The Discovery of T Cells and B Cells
July 24, 2026A mysterious protective substance in blood, pursued by generations of scientists for a hundred years — finally unmasked
—— From antitoxins to immunoglobulins: the most fascinating turning points in the history of antibody discovery.
I. 1890: the 'mysterious substance' in serum — von Behring and Kitasato's discovery
In 1890, two young men in Koch's laboratory — one German, one Japanese — were running an experiment that looked strange at the time: they extracted liquid from blood serum of animals infected with diphtheria or tetanus, injected it into healthy animals, then injected those healthy animals with lethal doses of diphtheria or tetanus toxin, to see whether they would still die. These two young men were Emil von Behring and Kitasato Shibasaburo. The results excited them: animals that had received immune serum were protected against the toxin. Moreover, this protection was 'transferable' — injecting immune animal serum into unimmunized animals also conferred protection.
This meant something in blood — some chemical substance — was responsible for providing this protection, rather than any specific cell or organ. They called this substance 'antitoxin.' This discovery directly gave birth to serum therapy — using immunized horse serum to treat diphtheria and tetanus patients. Before antibiotics appeared, serum therapy was one of the few effective treatments for these diseases, saving countless lives from the late nineteenth century into the early twentieth. Von Behring received the first Nobel Prize in Physiology or Medicine in 1901 for this discovery. Kitasato Shibasaburo was on the Nobel committee's candidate list, but ultimately was not selected — one of history's regrets.
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Von Behring and Kitasato's discovery answered a key question: 'Where is the protection?' The answer: in the blood, in a transferable chemical substance. This founded the concept of 'humoral immunity' and the application of serum therapy. |
2. Paul Ehrlich: architect of antibody theory and his 'magic bullet' dream
Paul Ehrlich was one of the most imaginative scientists of the late nineteenth and early twentieth centuries. His most famous contribution beyond immunology was discovering the first chemical therapy — arsenic compound 606 (Salvarsan) for treating syphilis (the first 'magic bullet'). In immunology, Ehrlich's most important contribution was proposing the 'Side-Chain Theory' (1897) to explain why antitoxins could specifically recognize and neutralize particular toxins. His idea: cell surfaces have various 'side chains' (today called receptors), with specific shapes. When a toxin enters, if its shape matches a side chain, it binds to that side chain, producing toxicity. Cells, to defend themselves, massively synthesize and release these side chains, letting them circulate freely in blood to preemptively bind toxins and neutralize them — these free-floating side chains are antitoxins (later called antibodies).
This theory was mostly wrong in its details (cells don't work that way; antibodies aren't side chains shed from cells). But it contained several very important correct intuitions: antibody-antigen binding specificity ('shape matching' concept); antibodies are soluble proteins circulating freely in blood; the immune system's function is to recognize and eliminate specific threats. Ehrlich's 'magic bullet' concept — finding molecules that can precisely target pathogens without harming normal cells — directly influenced the design philosophy of CAR-T cell therapy and targeted antibody treatment a hundred years later.
3. Karl Landsteiner: what antibodies can recognize is far beyond imagination
Karl Landsteiner, born 1868 in Austria, was a scientist who never stopped being curious. His most widely known discovery was the ABO blood group system (1901) — different blood types have different antigens on red blood cell surfaces, and corresponding antibodies will attack 'wrong' blood type red blood cells, causing transfusion failure. This discovery made safe blood transfusion possible; in 1930 he received the Nobel Prize. But Landsteiner's most far-reaching contribution to immunology was a series of experiments he performed in the 1930s on 'artificial synthetic antigens.' He attached simple chemical small molecules ('haptens,' as he called them) to proteins and injected them into animals — then discovered that the antibodies produced could precisely recognize these small molecules.
The significance of this discovery was revolutionary: it meant the immune system's recognition capacity was nearly unlimited — it could recognize chemical structures that had never existed in nature, recognize artificially synthesized molecules. This shattered a prevailing view at the time — that antibodies could only recognize biologically derived antigens. Landsteiner proved that antibody recognition is a chemistry problem, not a biology problem. This discovery's significance today: precisely because antibodies have this near-infinite recognition diversity (today we know it is produced by random recombination of B cell genes), targeted monoclonal antibodies for cancer treatment can be designed — these antibodies target various proteins on tumor cell surfaces, some of which the immune system has 'never encountered' in evolutionary history.
4. The Y-shaped secret: the afternoon antibody structure was cracked
In 1959, Rodney Porter at Cambridge University used a protease (papain) to 'cut' an antibody into three fragments — two 'Fab fragments' (Fragment Antigen Binding, the antigen-recognizing portions) and one 'Fc fragment' (Fragment crystallizable, the crystallizable portion). The same year, Gerald Edelman at Rockefeller University in the United States used chemical reduction to break antibodies into light chains and heavy chains. These two discoveries together gave the basic compositional model of antibodies: a Y-shaped protein, composed of two heavy chains and two light chains connected through disulfide bonds. The Y's two upper forks (Fab region) are the antigen-binding sites; the Y's base (Fc region) is the portion that interacts with other immune system components (like macrophages, complement). This Y-shaped structure is today one of immunology's most iconic illustrations. Edelman and Porter jointly received the 1972 Nobel Prize in Physiology or Medicine. Once the structure was known, immunologists could truly begin understanding: why antibodies have such diverse recognition capacities while being able to cooperate with other parts of the immune system; and how to artificially design antibodies to target specific molecules.
5. Monoclonal antibodies: making antibodies a mass-producible drug
After understanding antibody structure, a new problem emerged: natural serum antibodies are a mixture of many types (polyclonal antibodies) — against the same antigen, the immune system will produce dozens to hundreds of different antibodies, each recognizing a different 'epitope.' In 1975, Georges Köhler and César Milstein at the Cambridge MRC Laboratory invented a method for making 'monoclonal antibodies': fusing an antibody-producing B cell with an infinitely proliferating myeloma cell, producing a 'hybridoma cell' — this cell could both proliferate indefinitely (from the myeloma) and continuously produce the same specific antibody (from the B cell). Growing this hybridoma cell in large quantities yielded large amounts of a completely identical, single antibody targeting the same epitope.
This invention transformed antibodies from 'natural substances in serum' to 'precisely manufacturable industrial products.' Köhler and Milstein received the 1984 Nobel Prize. Importantly, they deliberately chose not to patent their method — they believed it was basic science research that should belong to all of humanity. This decision allowed the technology to be adopted by research institutions worldwide at the fastest possible speed, accelerating the entire biomedical field's development. Today, over half of all 'biologics' on the global pharmaceutical market are based on monoclonal antibodies — from rheumatoid arthritis treatments, to cancer treatments like Pembrolizumab and Trastuzumab, to COVID test strip antibodies. All of this began from that 1975 laboratory technique.
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Köhler and Milstein invented monoclonal antibody technology but chose not to patent it — believing it was basic science research that should belong to all of humanity. This decision let the technology be adopted at maximum speed globally, accelerating the entire biomedical field's development. A story about generosity in scientific history. |
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