Your Immune System Weaponized an Ancient Genetic Adversary

Written and Illustrated by: El Hebert '22
Edited by: Ashely Nee '22

Molecular biology brought us the vaccines that offer protection against Covid-19, but human scientists are a bit late to the party. In the adaptive immune system - the cellular army called upon by vaccines - your own personal genetic reshuffling apparatus runs constantly. And it has a very peculiar history.

At the center of your adaptive immune system are the B cells, specialized to manufacture weapons called antibodies. These Y-shaped proteins latch on with a lock-and-key fit to distinguish elements on the surface of their target - like the spikes studding the SARS-CoV-2 virus. Every B cell is born making a unique antibody, but it only produces enough to decorate its own surface.

Once in a while, though, the immune system’s infantry find themselves overwhelmed by an invader. At this point, they call for reinforcements by carrying samples from the field of combat to the waiting B cells. If they bump into one with an antibody that fits, that cell “activates,” ramps up production, and clones itself into a formidable force. Each clone can release 2,000 molecules per second! 

All those new, made-to-order antibodies provide a critical advantage to subdue the germs for good. And even years afterward, lingering B cell clones allow you to maintain immunity in the long term [1]. 

When you get vaccinated, your own body does all the heavy lifting. Vaccines simply offer a safe testing ground for the immune system to select and activate a well-matched B cell.

But on close inspection, this matching scheme doesn’t seem so elegant. It relies on the assumption that for any new threat, some B cell carries the perfect antibody blueprint. That requires a corresponding blueprint for every possible pathogen. In the mid-20th century, biologists began to confront the problem: there simply isn’t enough space in the human genome to fit that much information.

And to add further mystery, researchers discovered that variation only occurs in the antibody’s business end, at the tips of its Y shape. Underneath, they all share the same structure. In mature B cells, one single gene encodes the information for both the constant and variable regions, but that same gene in embryonic cells is missing the variable region [2].

A fully-assembled antibody in the characteristic Y-shape. Tokenzero, Wikimedia Commons.

Only one explanation was possible. Somehow, to ensure enough randomly-generated diversity, B cells have their DNA cut up and rearranged.
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Molecular biologists eventually mapped this process, and named it V(D)J recombination. Every antibody’s variable region is a mix-and-match of two, or sometimes three, different types of gene segment: V, D and J. These segments are samples from much larger regions - whole chunks of DNA that the cell discards after making its selection - and antibody genes contain several of each type. Imagine trying to create a new recipe by cutting some random pages out of three different cookbooks and pasting them together on their own. You could very well end up with an unmitigated disaster - in fact, many young B cells produce nonfunctional antibodies and must be eliminated by the body. But on the other hand, you might just invent your new favorite dish.

Your immune system has plenty of chances to get it right: mixing and matching can yield a staggering 100,000,000,000,000 (100 trillion) combinations.

DNA snipping is a carefully choreographed operation. The molecular machine for the job, called RAG, cuts and pastes only at particular marked sites, and recruits a whole entourage of helpers in the process. All vertebrates today - from anchovies to zebras - use RAG in their B cells, but it seems to have appeared in our lineage quite suddenly.

Insights from DNA sequencing point to a bizarre origin story. The sequence behind RAG, and the “cut here” markers in the antibody region, share striking similarities to a class of genes called transposons. These “jumping genes” move around within genomes via cut-and-paste systems just like the one used by B cells. They tend to be useless, or even dangerous - when they land, they can disrupt the rest of the DNA and cause disease. 

But by complete chance, in some ancestral fish, a transposon happened to hop into an antibody gene, and left behind its critical “cut here” markers when it jumped away again. Then, as the animal evolved, it domesticated the invader to make use of its unique function. These days, the vertebrate immune system can’t function without RAG [3, 4].

Living things adapt to survive. That’s as true for humans confronting the COVID pandemic today as it was for fish developing their antibody system over generations. Thanks to technology, viral  components can guide the immune system to protect you. And thanks to evolution, what was once a threatening parasite may now save your life.

​Works Cited:

[1] Alberts B, Johnson A, Lewis J, et al. Molecular Biology of the Cell. 4th edition. New York: Garland Science; 2002. Available from: https://www.ncbi.nlm.nih.gov/books/NBK21054/.

[2] Jung D, Alt FW. Unraveling V(D)J recombination: insights into gene regulation. Cell [Internet], 2004 Jan 23 [cited 2021 Apr 10]; 116(2), 299-311. DOI: 10.1016/S0092-8674(04)00039-X.

[3] Market E, Papavasiliou FN. V(D)J recombination and the evolution of the adaptive immune system. PLoS Biol [Internet], 2003 Oct 13 [cited 2021 Apr 10]; 1(1), e16. DOI: 10.1371/journal.pbio.0000016.

[4] Muñoz-López M, García-Pérez JL. DNA transposons: nature and applications in genomics. Current genomics [Internet], 2010 Apr 1 [cited 2021 Apr 10]; 11(2), 115-28. DOI: 10.2174/138920210790886871.

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