Today, monoclonal antibodies are a ubiquitous research tool. In fact, you’d be hard-pressed to find a lab without a freezer full of them. They have myriad uses from examining protein localization within a tissue (e.g., IHC), to isolating a particular protein out of a proteinaceous soup (e.g., WB, IP), or separating a specific cell population from the tissue milieu (e.g., FACS). They are such a fundamental part of so many research strategies that without them, there wouldn’t be many tricks left up our collective sleeve. So, it’s a little strange to think that we really haven’t had them at our disposal for all that long . . .
. . . setting the wayback machine for Cambridge, UK 1975 . . .
How was antibody technology first discovered?
The research community had already worked out that when an animal is faced with a foreign and potentially harmful protein (e.g., from a bacterium or virus), specialized immune cells (B Cells) leap into action, pumping out a complex cadre of antibodies to bind and eliminate the would-be threat. From a physiological standpoint, this polyclonal antibody arsenal clearly gives the animal its best shot at warding off an invading species. From an experimental perspective, however, the mechanism of how a polyclonal antibody army is mustered is rather difficult to dissect.
In Cambridge, biochemist César Milstein—later a Nobel laureate for his pioneering antibody research—led a lab focused on unraveling this exact mystery. In 1974, the prevailing hypothesis in Milstein’s lab was that somatic gene mutation was responsible for the hypervariable region of the antibody; and they were testing their theory by cloning and sequencing mutants from a myeloma (a tumor of the spleen) cell line.
They were failing to find mutations relevant to the hypervariable region, but the overall high somatic mutation rate within these cells suggested that they were on to something (spoiler alert: they were on to something). It was at this point that Georges Kohler joined the lab. Together, Milstein and Kohler reasoned that if they could combine the antibody-secreting properties of a normal B cell with the mutation rate and lifespan of the myeloma cell, then they would have a continuously dividing cell line that would produce a single antibody clone (re: the monoclonal antibody).
Such a research tool would allow them to examine how individual somatic mutations of the antibody might occur. They knew that fusing these disparate cells together while retaining the best properties of each was a long shot—but it worked. Importantly, they quickly realized that their new "hybridoma" lines were a research tool that could be exploited to answer a wider array of questions than those being asked in their own lab. Other researchers realized it as well and quickly jumped onto the hybridoma bandwagon... and the rest, as they say, was history.
Author’s note: There is actually quite a bit more to this story, so if you'd like the full story, check out Cesar Milstein’s Nobel Lecture. There is also a new book out on this topic that you might enjoy.
Additonal Resources
Read the Antibody Essentials blog series to learn more about how antibody technology evolved, current antibody production methods, and tips for selecting a reagent for your research.
