Part XI: Gerald M. Edelman, 1972 Prize in Physiology or Medicine
By Joseph Luna
To be immune is to be exempt. In the late 19th century, a physician named Paul Ehrlich gave a death-defying example of such an exemption by giving mice sub-lethal quantities of the deadly toxin ricin. Over time, these mice developed a specific resistance to ricin such that they survived when exposed to amounts that would kill a normal mouse. And yet, this ricin immunity was specific, as the super mice remained susceptible to other toxins. What made immunity so specific and how did it come about? With this experiment, Ehrlich joined a chorus of scientists that included Edward Jenner and Louis Pasteur before him to address immunity. It was upon these questions that the science of immunology was founded.
To explain how this might work in his ricin-proof mice, Ehrlich and others reasoned that the exposed mice begin to produce something that could counter the effects of the toxin—an anti-toxin. When it was shown that serum from an animal exposed to toxins or infectious diseases could be transferred to confer immunity in a recipient, this finding blossomed into the concept of a curative anti-serum. It was here that Ehrlich went further. Attempting to summarize the common thread that ran across exquisitely specific immunities against toxins, bacteria, parasites, or anything threatening, Ehrlich coined the term “antibody.” It was a specific antibody directed against a specific usually foreign substance, he formulated, that was the root cause of immunity.
Over the next five decades, the study of antibodies lay at the heart of immunology as researchers worked on how specific antibody reactions could be, how antibodies came about, how they could be inherited and passed along, and what exactly they were made of. Answering this last point briefly became a focus at Rockefeller in the 1930s, where chemical methods were first used to determine that antibodies were made of protein. But beyond this, key questions remained unsettled: what accounted for antibody diversity? Were specific antibodies structurally distinct by adopting different conformations or by having different sequences? In short: what does an antibody look like?
Sometime in 1955, a young captain in the U.S. Army named Gerald Edelman asked himself this question. Edelman was a medical doctor stationed in Paris, and when not attending to fellow soldiers at the hospital, Edelman would read medical and science textbooks for fun. Picking up an immunology textbook one day, he read page upon page of the foreign targets of antibodies—antigens—but almost nothing on antibodies themselves. After an extensive literature search on antibodies, Edelman reached an unsatisfying end. He decided to do something unusual: he applied to graduate school with the goal of studying antibody structure. Even more unusual, he chose not to go to a Harvard or a Johns Hopkins level institution, but instead entered a newly created graduate program at The Rockefeller Institute for Medial Research in 1957.
As a graduate student at Rockefeller, Edelman joined the lab of Henry Kunkel, an immunologist who was using chemical methods to study cancers of antibody producing cells, known as myelomas. Before he was able to answer what an antibody looked like, Edelman faced the two main obstacles of isolating a pure homogenous population of antibodies, if that were possible, and of trying to break them apart into their simplest pieces. On this second point, he succeeded by exposing commercially available or patient antibody fractions to the reducing agent urea. This chemical treatment would break a protein apart if its peptide chains were held together by disulfide bonds. Using urea and other reducing agents, Edelman observed that antibody mixtures could be broken down into roughly four pieces: two heavy and two light chains. But how could he know if these pieces weren’t an aberrant result of the chemical treatment?
There’s a famous saying in science: a day in the library can save a month in the lab. For Gerald Edelman, the next day in the library not only helped get at the question of how to get a pure population of antibodies, it also arguably helped send him to Stockholm. From his extensive knowledge of the literature, Edelman noticed that one of the light chains of his reduced antibody fragments was the same size as a mysterious protein first described by a physician named Henry Bence Jones in 1847. Back then, Jones described that many multiple myeloma patients excreted large amounts of a small protein in the urine, suggesting a way to diagnose the disease. With this in mind over a century later, Edelman made the leap to propose that Bence Jones proteins found in urine were probably individual light chains and were natural counterparts to the antibody fragments he had made. What’s more, since these homogenous proteins could easily be isolated in large quantities from the urine of myeloma patients, Edelman now had a source of a pure and naturally occurring antibody fragment. Taking antibodies from serum (even his own), breaking them down with urea and comparing them to Bence Jones proteins, Edelman found that all human antibodies had the same four pieces. With the help of others, Edelman solidified that although individual antibodies had different specificities, they were all made of the same four basic parts, and that only a small region was distinct in each antibody.
The now familiar Y-shape for the antibody molecule took another decade or so to flesh out and helped settle numerous scientific debates. By then, in such a short time Edelman went from student, graduating in 1960, to professor at Rockefeller in 1966.