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.
- By JAKE MILLER
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.
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.
