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Julia Merkenschlager’s immunology research explores how secrets of natural immunity can improve vaccines, treatment
By JAKE MILLER Research
5 min read
Image: Acrylic on paper by Sheryl Oppenheim
Work described in this story was made possible in part by federal funding supported by taxpayers. At Harvard Medical School, the future of efforts like this — done in service to humanity — now hangs in the balance due to the government’s announcements of a freeze on payment for federally funded research and an end to new grants across Harvard University.
To fight off viral and bacterial invaders, immune cells known as lymphocytes generate antibodies that specifically recognize and bind to these invaders, neutralizing them directly or marking them for destruction by other immune cells. But how does the body learn to fend off invaders it hasn’t encountered before?
Julia Merkenschlager, who became a member of the faculty of immunology in the Blavatnik Institute at Harvard Medical School in October 2024, is working to unlock the secrets of how the immune system selects the best antibodies for the job through a remarkable process of cellular competition and collaboration.
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Deepening our understanding of this fundamental process can guide the way to new therapies that augment the body’s natural lines of defense to fight off serious infections.
Merkenschlager spoke with Harvard Medicine News about the motivators and mysteries that drive her work, which has been supported by federal and philanthropic funding.
Harvard Medicine News: What problems do you hope to solve by illuminating the mechanics of acquired immunity?
Julia Merkenschlager: We still lack effective protection against some of the world’s deadliest infectious diseases. I see my role as helping reveal the fundamental steps that immune cells take to produce effective antibodies against the pathogens that cause these diseases so we can design better ways to protect against them. You might say we can’t really write our own music until we know the notes.
As a field, immunologists have discovered a subset of individuals exposed to HIV who make antibodies against the virus that prevent them from getting AIDS. They’re called elite controllers because their immune systems, unlike the majority of others, can control HIV. If we had a vaccine that could induce all people’s immune systems to produce those antibodies, we could prevent new HIV infections, or the progression to AIDS. Many researchers have tried, but it has proven very difficult to reliably produce those gold-standard antibodies in experimental models.
The changes to immune cells that are needed to generate a suitable antibody for HIV are much more complex than for many other viruses. Elite controllers seem to have something special that makes their antibody production process different. It would be invaluable to know what the special something is so we can learn from it and leverage it.
HMNews: What do and don’t we know about how the immune system learns to fight a pathogen it’s never met before?
Merkenschlager: We’ve known the outlines since the 1960s, but the details have remained mysterious.
The process starts when the immune system encounters an antigen it doesn’t recognize. That’s a small protein that can indicate potentially dangerous foreign objects like viruses and bacteria. A group of immune cells called B lymphocytes makes what we call a starting antibody, which does a fair job of binding to that given antigen. The cells then enter a process of maturation where they transform that raw starting antibody into a specialized, highly effective antibody that can bind tightly to the antigen, neutralizing it or marking it for destruction to protect the body.
This maturation process involves the B cells introducing little edits to their antibodies and then testing these new variants to see if they’re better or worse at binding to the antigen target. The worst ones get eliminated, the middling ones get sent back for more edits, and eventually, the really good ones are mass-produced.
After the threat is cleared, some of the highly successful B cells become memory B cells, called sentinels, standing watch for years in case the enemy returns, while others become dedicated factories, known as plasma cells, quietly churning out protective antibodies from deep within the bone marrow. Together, they help preserve the ability to make these excellent antibodies in case the invader or relatives of the invader return.
HMNews: Your research focuses on something called the germinal center. What is that?
Merkenschlager: The whole B-cell antibody maturation process unfolds within structures known as germinal centers that occur in lymphatic tissues throughout the body.
If you look under the microscope, germinal centers resemble galaxies made up of constellations of cells. Within these constellations, the stars are B cells that are competing with one another to see which can create the antibody that binds best to the antigens they encounter.
The specialized conditions in germinal centers make all this possible. For example, they’re rich in mutagenic signals that push B cells to tweak the genetic machinery they use to edit their antibodies, increasing the chances of discovering a better fit for the target
HMNews: That covers how the B cells compete with one another to create the best new antibody. Where does the collaboration come in?
Merkenschlager: It turns out the B cells have some help from another type of lymphocyte, specialized T cells, called helper cells. These guide the B cells and make pivotal decisions about which B cells survive, how many chances they get to mutate, and when to begin mass production of the B cells that make the best antibodies. If you think of B cells as musicians, these T cells are the conductors carefully orchestrating the maturation process with precision and harmony.
HMNews: What is an unsolved question you’ve helped answer?
Merkenschlager: What stops successful B cells from mutating further while they swim in a sea of mutagens has been an enduring mystery for more than half a century. We shed some light on it in a collaborative recent study I co-led as a postdoctoral fellow at The Rockefeller University in the lab of Michel Nussenzweig.
We found that helper T cells push the best B cells through cell division more quickly, which reduces their exposure to the mutagens. It’s a simple, elegant solution. Speeding up reproduction means you get more copies of the best B cells while limiting the chance that a random mutation will ruin a good antibody.
HMNews: How did collaboration allow you to crack this decades-old mystery? It seems like this is an important theme for you in research and in life.
Merkenschlager: We partnered with theoretical physicists at Princeton to gain from their specific expertise in mathematical modeling. There’s great benefit to including all kinds of perspectives in scientific work. It is essential for solving the most complex problems.
My interest in collaboration and competition isn’t limited to the storyline playing out in the germinal center. These different ways of being in the world are a part of our daily lives: the competitive drive and the need to work together. I have thought about this since I was little, living alongside my younger siblings.
I love working in the lab alongside new scientists at the start of their careers. I also love engaging with artists outside the lab, sharing my work, and exploring how their creative perspectives can offer new ways of thinking about biology.
HMNews: Tell me more about how you think about art and science.
Merkenschlager: My dear friend Sheryl Oppenheim makes work that features non-representational marbling. It evokes imagery that resonates with scientific themes. Many scientists see reflections of their research in her pieces—such as fluorescent lymphocytes, cellular apoptosis, histology, condensates, or chlorophyll.
When I was younger, I thought I’d become an artist. I spent countless hours learning to draw, and one lesson has always stayed with me: keep looking at the thing you are drawing! So, at first, you study the object closely, carefully deciding where each line should go on the paper. But once you think you’ve understood it, you stop observing, you look down at the page and just keep drawing. And that's when you make a lot of mistakes.
So I think there’s a real power in not knowing something because you feel compelled to observe everything. Small things. Big things.
I still draw, but more importantly, I try to bring that same mindset into science. Maintaining a sense of curiosity and fresh eyes is essential when asking fundamental questions about how the machinery of life works.
This interview has been edited for length and clarity.
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