Dr. Götz Ehrhardt: The Lamprey TimeMachine -Unlocking theSecrets ofJawless Immunity

In the murky depths of the Great Lakes, the sea lamprey is often seen as a nightmare, an invasive parasite that latches onto prey and refuses to let go. But to Dr. Götz Ehrhardt, an Associate Professor in the Department of Immunology at University of Toronto, these “living fossils” are more of a biological time machine.

While humans and all other jawed vertebrates rely on the adaptive immunity toolkit of antibodies and T-cell receptors, lampreys took a different evolutionary path 500 million years ago. We sat down with Dr. Ehrhardt to discuss how studying these ancient creatures is revolutionizing our approach to biomarkers, oral therapeutics, and the very definition of “memory” in the immune system.

You have spent much of your career studying the lamprey model. What drew you to such an unconventional model, especially given its reputation as an invasive pest?

Chance, really. I did my postdoc in the lab of Max Cooper. And Max had worked as a postdoc in Bob Good’s lab. Bob Good’s work in lampreys showed that, when immunized with heat-killed bacteria, the animals produced agglutinins a fancy word for “clumping”, essentially indicating that there were antibody-like molecules in the serum. They also showed skin allograft rejection with accelerated kinetics upon repeat grafting, suggesting a cell-mediated immune response with memory.

For a long time, the adaptive immune system was considered an invention of the jawed vertebrates, from humans all the way back to cartilaginous fish, like sharks and rays. Jawless vertebrates were thought to make do with innate immunity alone. People had been searching for decades for an adaptive immune counterpart like antibodies (or B cell receptors), and T cell receptors in lampreys and returned empty-handed every time.

That changed when a brilliant and driven postdoc named Zeev Pancer joined the Cooper lab. He was the perfect example of ‘right person at the right time doing the right thing’. He did the foundational work that led to the identification of what we now call variable lymphocyte receptors, the VLRs, which are antibody-like counterparts in lampreys. Call it chance, but I was in that lab when it happened.

How do these VLRs differ from the “conventional” antibodies we have in our own bodies?

Our antibodies are built on the immunoglobulin fold: a modular beta-sheet sandwich, that has been repurposed and elaborated across virtually all jawed vertebrates. VLRs use an entirely different scaffold: the leucine-rich repeat, which assembles into a solenoid, a curved, concave horseshoe shape. The antigen engages residues lining the inner, concave surface, as well as a loop protruding from the conserved C-terminus, a bit like our thumb if we were to form a “C” shape with the palm of our hand. Because the architecture is so different, they can “see” things our antibodies cannot. These are truly distinct solutions to the same problem of antigen recognition.

Given structural differences, can VLRs recognise antigens that conventional antibodies cannot?

With a large enough library, you can probably make a conventional antibody to almost anything. But there are two meaningful reasons to think VLRs can access targets that are practically difficult. First, the different protein architecture may allow recognition of certain carbohydrate epitopes that may be less accessible to immunoglobulin structures. Second, the mammalian immune system must maintain tolerance to self; a lamprey does not share that constraint.

I can answer this with an example. My lab works on memory B cells, adaptive immune cells that help the body “remember” past infections. For a long time, there was simply no reliable marker to isolate them. Justin Chan, a former graduate student in my lab, used a VLR display library to search for a binder that could distinguish memory B cells and plasma B cells from everything else. He found one. The marker turned out to be MHC class I, a molecule found on almost every nucleated cell in the body. The result seemed nonsensical at first. Why would it be selective? It took considerable work to unravel, but the VLR was recognising MHC class I specifically in the context of tyrosine sulfation, a post-translational modification that had never been described in this context before. This opened an entirely new line of investigation that we are still actively pursuing.

The theme of this issue is “Built to Survive.” You have found that VLRs are remarkably hardy. How does that translate to medicine?

This is where it gets really exciting. When we first tried to purify VLRs, we used the standard protocol of eluting an antibody from its antigen using a low pH (~ pH 2.5). Usually, that’s enough to make the antibody let go. With VLRs, nothing happened. We tried 3M magnesium chloride, 5M lithium chloride, and even hydrochloric acid at pH 1.5. Miraculously, the VLR stayed stuck. We eventually had to go up to pH 12.5 using sodium hydroxide to get it to let go. And even then, once we neutralized the pH, the VLR could bind again. This is something a conventional antibody simply cannot do.

Because they are so resistant to low pH, they are ideal candidates for oral therapeutics. They could potentially survive the transit through the stomach and act directly in the gut to treat gastrointestinal diseases.

Immunology as a field is quite mouse-centric. What would you say to students who want to work outside that paradigm?

Firstly, keep your mind open. And go to conferences that are a little off the mainstream. There is a meeting called the North American Comparative Immunology conference (NACI) where you will encounter very unusual and exciting science.

Immunology had its origins in comparative biology; there were beautiful model systems across the tree of life. Developmental biology kept its zebrafish and Drosophila. Genetics kept its yeast. Immunology, for understandable reasons, became the science of the mouse. You need a model that reflects human physiology, with a rapid reproductive cycle. And a mouse is perfect for those reasons. While it has served us extraordinarily well, but it narrows the scope. Sometimes the most useful tool is not the closest relative. My lamprey work began because I was trying to solve a problem in my own research area, finding a marker for memory B cells, and I looked elsewhere for the tool. And that worked out!

Last question: What is one thing about lamprey immunity you wish more immunologists knew?

That lampreys are an excellent system for generating really interesting antibodies!

Fun fact: In Portugal, they are a seasonal delicacy and served as ‘lamprey stew on rice’. If you have worked with the animals in the lab, you see precisely what ends up on your plate. It does not help improve your appetite. The accompanying red wine, however, is exceptional! Moral of the story: lampreys are great to have in the lab, not as great on the dinner plate.