by Aleks Prochera

figures by Jovana Andrejevic

Imagine wading through the fresh waters of the Paleozoic era over 300 million years ago. You bump into various ancient marine creatures from fishes adorned with horseshoe-shaped shields to aquatic scorpions the size of a modern-day seal. Around you, however, there also exists an unseen world teeming with microbes: viruses, bacteria, and fungi. Despite their deceivingly microscopic size, these organisms pose a major threat to your existence.  

This experience is that of a lamprey, one of the first vertebrates (animals with a spine) to step foot, or rather, wag an eel-like body in the Earth’s oceans. These creatures, just like all other animals, employ their immune systems to protect themselves against infectious microbes. Until recently, however, the details of their immunity have been poorly understood, a mystery that might help us better understand how our own internal defenses came to be. 

Only in the past few decades have scientists started to tackle this enigma by observing the lamprey’s immune system. Now, for the first time, they are turning to cutting-edge experimental methods to better understand the animals’ immune defenses. In a new study published in the journal Science Immunology, scientists employed genetically engineered lampreys to identify one of the ancient components of vertebrate adaptive immunity.

Immunity that adapts 

At any given time, trillions of white blood cells are patrolling your body that protect you from disease-causing microorganisms, or pathogens. Among these are white blood cells called T and B lymphocytes, which are part of your body’s adaptive immune system (Figure 1). Their role is to recognize and, ultimately, eliminate any harmful entity that comes your way. 

To recognize these harmful microorganisms, every T and B cell is endowed with a unique, one-of-a-kind sensor on its surface called a receptor. Every one of these receptors has the capacity to detect a single, distinct characteristic of an invading microbe, such as the molecules which decorate the pathogen surface and mark it as foreign and dangerous. Thanks to this exquisite specificity and selectivity in telling pathogens apart, your body can mount a deliberate, targeted counterattack to eliminate the invading pathogen.

The receptors that T and B cells use for pathogen recognition are formed in a special process of chopping, reshuffling, and stitching together DNA.  The resulting reshuffled DNA gives rise to the T- and B- cell receptors through which these lymphocytes interact with the microorganisms around them (Figure 1). Without these receptors, the T and B cells not only cannot perform their function, they actually do not survive at all! Talk about a true commitment to one’s work.

Thanks to decades of research on classic laboratory model animals such as mice, scientists developed a sound understanding of how adaptive immunity works. This knowledge has been transformative when it comes to the ways we approach numerous maladies. Yet, despite these impressive advances, a key question remained: how did these elaborate defense mechanisms come to be?

The origins of adaptive immunity 

With this unresolved question in mind, some immunologists resolved to “go back in time” and trace the evolutionary origins of our immune system.

Modern-day vertebrates, from fish and amphibians to mammals like us, rely on the targeted defense mechanisms provided by T and B cells. On the other hand, invertebrates, animals without a bony skeleton (think insects, snails, corals, and many others) possess none of the components of the traditional adaptive immune system. So did T and B cell-mediated immunity coincide with the appearance of a spine? In other words, did even the earliest vertebrates have T and B cell-mediated immunity, or did those kinds of internal defenses arise later in the vertebrate family?

In 2002, Dr. Max Cooper’s research group published the first in a series of papers that tackled this question. They decided to study one of the oldest vertebrates still around today: lampreys, jawless fishes known for their intimidating concentric rows of teeth. The researchers demonstrated that lampreys possess an adaptive immune system similar to ours. The researchers showed that lampreys also use T- and B-like cells for defense against pathogens. And their T- and B- cells also employ customized receptors to detect specific pathogens. 

Cooper’s work suggested that all vertebrates, from ancient lampreys to modern-day humans, rely on similar adaptive strategies for defense. Their research also established the animal as a new laboratory organism in the immunologists’ toolbox. Until recently, however, the specific components of the lamprey’s immune system and how these factors relate to higher organisms remained an open question.

Genetically modified lamprey sheds light on the origins of adaptive immunity

That changed in March 2020 when the laboratory of Dr. Thomas Boehm from the Max Planck Institute of Immunobiology and Epigenetics discovered a factor necessary for lamprey’s adaptive defenses. The study pointed to cytidine deaminase 2 (CDA2 for short), a protein molecule produced by the lamprey’s B-like cells, as one of the earliest components of the adaptive immune system.

To test whether CDA2 is one of the key players in the formation of ancient adaptive immunity, the researchers eliminated the factor and explored the resulting changes to the lamprey’s internal defenses. To do that, they adapted CRISPR/Cas9, a cutting-edge method of genetic engineering, to the lamprey larvae and, thus, generated animals incapable of producing the CDA2 protein (Figure 2). 

Compared to normal lampreys, the animals lacking CDA2 could not produce B-cell receptors. Moreover, when the researchers looked for B-like cells in the creatures’ tissues, where they should see loads of them, they didn’t find any (Figure 2). Since B-cells do not survive without their sensors, these observations suggested that CDA2 is involved in the formation of receptors in the lampreys’ B-like lymphocytes.

These findings demonstrate that lamprey’s CDA2, just like a similar factor from higher vertebrates, plays a role in generating adaptive defenses. It is the first time a particular protein has been unequivocally shown to be a component of the lamprey’s adaptive immune system. The discovery points to the existence of shared machinery involved in the formation of this type of immunity and illustrates just how old it actually is. The research also heralds a new era in the study of evolutionary immunology. It is certainly not the last time lampreys, especially the genetically modified ones, give teeth to new theories of immune system evolution. 

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Aleksandra Prochera is a Ph.D. student in the Harvard Immunology Program. You can find her on Twitter as @Aleks Prochera.

Jovana Andrejevic is a fourth-year Applied Physics Ph.D. student in the School of Engineering and Applied Sciences at Harvard University. 

For more information:

• Want to understand more about our internal defense system? Check out BiteSized Immunology’s guide to the immune system and the Immunobites website.
• Interested in diving deeper into the origins of our immune system? This article provides a short and sweet overview of evolutionary immunology and why it’s worth studying it.
• This recent scientific review from the authors of the study is a comprehensive summary of the current state of the field. 
• Check out this article about research from Max Cooper’s group to learn more about how ancient aquatic creatures are informing human therapeutics.