The history of antibodies
Kirsty Strawbridge explores the experiments that led to the discovery of antibodies
Antibodies, also known as immunoglobulins, are proteins in the blood that are created by B cells in response to proteins called antigens, which the body recognises as ‘non-self’. Understanding antibodies is useful because it means that we can develop blood tests to diagnose illnesses.
Imagine you’re a doctor and a patient comes to see you with a fever, muscle aches, a sore throat and a general sense of lethargy. These symptoms might suggest that your patient’s been infected with Mycoplasma pneumoniae, which should be treated with antibiotics as quickly as possible – or they might indicate influenza, which should never be treated with antibiotics because it’s caused by a virus.
One way to tell the difference between the two, or any other pair of illnesses, is to look at your patient’s blood to see what type of antibodies they are producing. This should reveal which antigens are in their system.
Antibodies also play an important part in the development of several diseases. They can render infectious organisms harmless by attaching to their antigens.
Von Behring, Ehrlich and poison-resistant mice
The term Antikörper (‘antibodies’) was introduced in Paul Ehrlich’s ‘Experimental Studies on Immunity’ in 1891. But his work was pre-dated by Emil von Behring’s investigations into “serum therapy” to treat diphtheria and tetanus in 1890.
Von Behring’s work was based on Emile Roux’s discovery of the diphtheria toxin and was hugely influential at the time: in a speech in 1899, New York’s leading public health official, Hermann Biggs, said that “among the remarkable developments in medicine during the last ten years none has been more important in its practical value, nor more revolutionary in its effect on therapeutic possibilities and conceptions than the discoveries in serum-therapy”. In 1901 von Behring received the first Nobel Prize in Physiology or Medicine for the antitoxin he developed.
Ultimately, though, von Behring’s serum therapy was only useful against a small number of diseases. Despite his important role in reducing diphtheria, which is still extremely rare in most countries today, his work was eventually overshadowed by the introduction of antibiotics and the work of Robert Koch and Paul Ehrlich.
Ehrlich was fascinated by toxicity and immunity. Independent of von Behring’s work, Ehrlich – a great fan of Sherlock Holmes and other detective novels, and a meticulous researcher – began to conduct rigorous experiments using mice.
At first, he fed the mice cocaine; later, he started testing their resistance to different amounts of ricin, one of the world’s deadliest toxins. The amount of ricin that it takes to kill a laboratory mouse is extremely small, but Ehrlich gradually increased the doses for individual mice until they could resist doses that would have been lethal if they had been administered straight away.
Even more impressively, Ehrlich eventually produced mice that could survive doses of ricin that were hundreds of times stronger than the lethal dose for mice that hadn’t been exposed, making it clear that something in the immune system of the mice was developing resistance to the toxin. He also began to explore whether the immunity was specific, finding that mice that could withstand large amounts of ricin were just as susceptible to abrin (another potent toxin) as mice that hadn’t been exposed to either and that abrin exposure had no effect on ricin resistance.
The underlying concept was similar to smallpox vaccination, introduced by Edward Jenner in 1798. What separated Ehrlich’s work from Jenner’s was his insights into the mechanisms of immunity, particularly the side-chain theory that he proposed in 1900. The theory suggested that side chains within the cells react with antigens and bind them – fitting like a lock and key – to create antibodies, which then travel around the body in the blood.
Edelman and Porter
After the introduction of Ehrlich’s side-chain theory, researchers continued to work on antibodies but made few significant discoveries over the next 50 years. “Up to the year 1959,” reported the Karolinska Institute in 1972, “our knowledge of [antibodies’] nature and mode of function was very vague and incomplete, in spite of a century of research.”
In 1959, though, Gerald Edelman and Rodney Robert Porter revealed their independent discoveries about the chemical structure of antibodies, which led to them jointly receiving the 1972 Nobel Prize in Physiology or Medicine.
Edelman got into immunology in an unusual way: “as a result of boredom”. He was serving in the army in Paris when he read a book about the body’s reaction to antigens and realised it didn’t explain exactly how antibodies function. That’s when Edelman made a decisive prediction about his return to America: “When I go back and do research, I’m going to work out how antibodies work.”
Both Edelman’s work and Porter’s focused on breaking antibodies down into smaller parts so they could be handled and studied more easily, which had important implications for diagnostics and therapy.
Porter used the enzyme papain to split antibody molecules into three parts, and Edelman focused on breaking the disulphide bridges holding the molecule together. Their work revealed that antibodies consist of two pairs of chains – two short ‘light’ chains and two ‘heavy’ chains, which are about twice the length of the light chains – held together in a ‘Y’ shape by disulphide bridges.
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