The NFT
I chose to mint this slide because it represents a unique moment in the history of antibody research. At the former home of Benedictine monks in Venice, this slide was shown to a future Nobel Laureate and other researchers whose contribution to science was a foundation for vaccine efforts, including with COVID-19. What is notable about this slide is that it shows data from a study from a Nobel Laureate’s lab 30 years prior and supports a radical change in thinking about antibody diversity.
Ultimately, it also showcases how we as scientists have difficulty accepting new perspectives on matters previously considered settled. It is one that is somewhat warranted and somewhat antithetical to the idea of science, in which we are supposed to constantly evaluate our held beliefs against new data. While I am personally not sure what the correct amount of skepticism is, I wanted to mint this slide to immortalize that concept and the duality of dogma and innovation in science.
Introduction
Its hard to imagine that this is the only time in history in which a majority of people know what an antibody is. They know that antibodies form after vaccines and infections and protect them if they are ever exposed again. Integral to this is a Darwinian process of mutation and selection.
In my work, I look at these mutations and argue for method of mutation that has been largely ignored as a potential source of diversity. What follows below is a story, full of scientific history, of the one of the most intriguing times we had presented this work.
The Conference
In 2017, I was on the heels of submitting my first dissertation paper. Like any graduate student writing their first draft of their first paper, the paper had pros and cons - although much more of the latter. In any case, I was determined to continue to get feedback from the field and improve the paper accordingly. One of the best ways to do that was to “talk” directly to my reviewers, i.e. attend a conference. In my field, this was the surest way you could have conversations with individuals who might end up being your reviewers when you submit your paper for peer review.
That said - it so happens that my PI, Dr. Joshy Jacob, was invited to a conference that was specific for the germinal center (see Research link above). One day he walks into the lab and tells me of this. Not one to waste an opportunity, I immediately looked into ways that I could attend. Luckily, I was an NIAID predoctoral fellow with some left over discretionary funds that could be used to cover the cost of attendance and travel. With that I registered for the conference later that year.
To say I was excited was an understatement. This conference - the 19th International Conference on Lymphatic Tissues and Germinal Centers in Immune Reactions (GCC) - was a meeting of the who’s who of antibody research. In attendance were larger than life researchers such as Tasuku Honjo (wins the Nobel Prize in Medicine the following year in 2018), Klaus Rajewsky (Robert Koch Prize Winner and preeminent B cell biologist), and Antonio Lanzavecchia (noted contributor to T cell and dendritic cell biology, cited over 112,708 times). This only scratches the surface of the wealth of scientific minds gathered however.
The Venue
These immunological giants gathered at San Servolo Island in Venice, Italy from September 14-17th, 2017. It was by and far the most interesting venue for a scientific conference that I had ever attended before and since then. Former Benedictine monastery and later psychiatric hospital, the island lies near the mouth of the Giudecca canal and is only accessible via boat that would arrive once an hour. To those unfortunate enough to miss the last ferry for the day, they would be marooned on the island for the night.
The conference began promptly each day at 8am. During my time in Venice, I stayed on the main island and would take the ferry each morning to arrive for the opening sessions.
The Presentation
On the morning of September 16th, I arrived early via ferry. As the ferry glided through the Venetian lagoon, my nerves were wracked - Today was the day my PI would present my work. The day prior I had presented a poster of the work and was met with stern resistance. Thoughts flashed in my head about what my PI would face.
Arriving a couple of minutes before the session began, I walked my PI through the major points of the presentation I had made days prior. He seemed nervous but assured me that this was how he always was before a presentation. We then went over the most pivotal slide of the presentation. This was a slide that showed historical evidence of gene conversion. A slide of work of a Nobel laureate’s lab. A slide about one of the most fundamental aspects of the antibody response.
The Slide
The primary reason that the COVID-19 vaccines require a second immunization one month after the first shot is due to the concept of affinity maturation. Simply put that is the phenomenon of antibodies becoming better at binding to the offending pathogen over time. The way this occurs is through repeated mutations to antibodies in a person’s body. The best ones are selected to survive and the weakest binding antibodies are eliminated. This concept of increasing mutations to get a better antibody was distilled in a paper from Claudia Berek (an organizer of this conference) and Cesar Milstein (Nobel laureate, famous for hybridoma technology that allows us to produce antibody-based drugs). This paper “Mutation Drift and Repertoire Shift in the Maturation of the Immune Response” found that antibodies selected to respond to a particular immunization had BOTH a high affinity mutation (making the antibody better) as well as a mutation that did not change the affinity (did not make the antibody better or worse).
When I performed an analysis of this data, I found that both mutations were explainable via the gene conversion mechanism with another gene. Further, we found that a “silent” mutation (i.e., one that has no effect on the antibody amino acid sequence) was also predicted by the gene conversion mechanism. The slide ushered in a more serious tone around our investigation of gene conversion. If we had been wrong, how was it possible that we could explain the past? Later, Antonio Lanzavecchia approached my PI and stated while he retained some skepticism, he also believed that we could not simply dismiss the findings.
Participants from the 19th GCC. Image credit: IFOM