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Knight in lab: In days of yore, postdoc armed with quaint research tools found immunology's Holy Grail

charging knightA human has only about 25,000 genes. So, it’s tough to imagine just how our immune systems can manage to recognize potentially billions of differently shaped microbial or tumor-cell body parts. But that's precisely what our immune systems have to do, and with exquisite precision, in order to stomp invading pathogens and wanna-be cancer cells and leave the rest of our bodies the heck alone.

How do they do it?

Stanford immunologist Mark Davis, PhD, tore the cover off of immunology in the early 1980s by solving that riddle. As I wrote in  "The Swashbuckler," an article in the latest issue of Stanford Medicine, T cells are one of two closely related, closely coordinated workhorse-warrior cell types that deserve much of the credit for the vertebrate immune system’s knack of carefully picking bad guys of various stripes out of the lineup and attacking them:

[Q]uite similar in many respects, B cells and T cells are more like fraternal than identical twins. B cells are specialized to find strange cells and strange substances circulating in the blood and lymph. T cells are geared toward inspecting our own cells for signs of harboring a virus or becoming cancerous. So it’s not surprising that the two cell types differ fundamentally in the ways they recognize their respective targets. B cells’ antibodies recognize the three-dimensional surfaces of molecules. T cells recognize one-dimensional sequences of protein snippets, called peptides, on cell surfaces. All proteins in use in a cell eventually get broken down into peptides, which are transported to the cell surface and displayed in molecular jewel cases that evolution has optimized for efficient inspection by patrolling T cells. Somehow, our inventory of B cells generates antibodies capable of recognizing and binding to a seemingly infinite number of differently shaped biological objects. Likewise, our bodies’ T-cell populations can recognize and respond to a vast range of different peptide sequences.

In the late 1970s, scientists (including then-graduate student Davis, who is now director of Stanford's Institute for Immunity, Transplantation and Infection) unraveled the genetic quirks behind B cells' ability to recognize a mind-blowingly diverse  set of different pathogens' and tumor-cells' characteristic molecular shapes. As a follow-on, Davis and a handful of colleagues - working with what would today be considered the most primitive of molecular-biology tools - isolated the gene underlying the T-cell receptor: an idiosyncratic and very important surface protein that is overwhelmingly responsible for T cells' recognition of myriad pathogen- and cancer-cell-specific peptide sequences. And they figured out how it works.

The result? (Again from my article:)

With the T-cell receptor gene in hand, scientists can now routinely sort, scrutinize, categorize and utilize T cells to learn about the immune system and work toward improving human health. Without it, they’d be in the position of a person trying to recognize words by the shapes of their constituent letters instead of by phonetics.

Previously: Stanford Medicine magazine traverses the immune systemBest thing since sliced bread? A (potential) new diagnostic for celiac disease, Deja vu: Adults' immune systems "remember" microscopic monsters they've never seen before, Immunology escapes from the mousetrap, Immunology meets infotech and Mice to men: Immunological research vaults into the 21st century
Photo by davidmclaughlin

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