Stanford Medicine Scope - January 19th, 2021 - by Bruce Goldman
A sizable chunk of the U.S. population has had a sizable chunk of tissue -- their tonsils -- excised from their throats. Each year in the United States alone, about half a million pairs of tonsils are removed, destined for disposal as medical waste.
But a group of scientists led by Stanford systems-immunology pioneer Mark Davis, PhD, has changed that destiny for some spurned tonsils, transforming those olive-sized organs into living immunology labs in a dish.
There, as documented in a recent Nature Medicine study, these discarded tonsils have taken on a new career as testbeds for vaccines targeting COVID-19, influenza and other infectious diseases.
Here's how it works.
Children and some adults typically undergo tonsillectomies because their tonsils are blocking their air passages and disrupting sleep, or have become chronically infected or inflamed.
But tonsils, when they're healthy, serve a grand purpose: As Davis told me, "Tonsils are basically giant lymph nodes in your throat."
Lymph nodes -- distributed throughout the body and connected by a vast interwoven network of canals that washes over our tissues -- are the Grand Central Stations of the immune system.
These organs play host to, and indeed are mostly composed of, large numbers of diverse, highly interactive immune cells called lymphocytes. Lymphocytes mount precision assaults on microbial pathogens or suspected tumor cells while leaving our healthy cells unscathed. One such operation is the production of antibodies, proteins that can bind to distinct features of a specific pathogen, putting it out of commission.
Discarded tonsils are a treasure trove of lymphocytes -- a billion of them per each tonsil -- with all the diversity and organization incumbent in a living person's lymph node.
Instead of letting those gullet-gripping goldmines be tossed out, Davis, his then-postdoc Lisa Wagar, PhD (now on the University of California-Irvine faculty), and colleagues spirited a shipment off to their lab (with patients' or their parents' permission).
The scientists disaggregated each tonsil into its constituent cells, and placed the cells in a culture dish. There, the cells spontaneously reassembled into myriad minuscule clusters of a mere five to six million cells apiece, their diameters less than one thousandth the thickness of a human hair.
That small size conferred upon these clusters a high surface-to-volume ratio that let them get all the oxygen and nutrients supplied by the surrounding culture medium. The reassembled nanoscale clusters mimicked the anatomical organization of living lymph nodes' germinal centers, where antibodies are born: precise arrangement of concentric layers of different collaborating cell types.
In a series of experiments described in the study, the clusters reproduced several critical functions of lymph nodes.
"They did all the things they're supposed to do," Davis said.
Importantly, when they were incubated with vaccines -- which stimulate lymph nodes to produce antibodies that can disable specific pathogens -- the little clusters did just what they were supposed to do: They produced antibodies against the targeted pathogens.
The scientists tested the tonsil clusters' responses to several vaccines -- including two for influenza; one for rabies; another directed at measles, mumps and rubella; and an experimental construct being developed for COVID-19.
In response to all of these vaccines, cell clusters from some donors pumped out pathogen-specific antibodies, while clusters from other donors did not.
This suggests the new system may be able to predict what proportion of people given a potential vaccine would mount a strong immune response to it -- and, perhaps, even predict just who wouldn't.
To see what portion of the population would mount a good antibody response to a potential vaccine formulation, for example, the formulation could be added to several separate dishes, each containing clusters derived from a different donor's tonsils, Davis said. Then the same process could be repeated with a second formulation, a third one, and so forth.
The reconstituted-tonsil system could change the way scientists test vaccines, Davis told me.
"Developing a vaccine the traditional way is costly," he said. "So vaccine developers are forced to narrow their candidates down to just one that they think is the best, based mainly on mouse studies."
The new system is not only cheaper and faster, Davis told me, but because it's entirely human, it's also likely to be more accurate in estimating just how a potential vaccine will perform in a live human.
In short, mice are nice, but mice and people are different: "Mice don't even have tonsils," Davis noted.