Learning from Llamas: Biomedical Discovery Inspired by the Animal Kingdom

Modern approaches in medicine are increasingly focused on manipulating the human body’s natural immune system.¹ These approaches are referred to as “immunotherapy.” Advances in immunotherapy have greatly benefited individuals with diseases such as cancer and autoimmunity, but there are still many opportunities for improvement. The immune systems of animals are a promising source for inspiration.²

The immune system is comprised of white blood cells and is conceptually divided into two types: the adaptive and the innate.³ The innate immune system is ancient, present in animals all the way down to fruit flies, while the adaptive immune system is relatively newer, present only in some vertebrates, such as mammals.

The innate immune system is constrained by evolution to only recognize obvious threats, such as the cell wall of a bacterium. The adaptive immune system, however, is virtually unlimited in what it can target. Appropriately, adaptive immunity relies upon the innate system to trigger the alarm. Upon activation of innate immune cells, adaptive immune cells are called into action and trigger their defense program. The relationship between innate and adaptive immunity is like an airport security dog and its police officer handler. Although the dog (innate immune cell) is menacing, the handler (adaptive immune cell) has the real power – but that police officer won’t be activated unless the dog signals.

One of the most powerful adaptive immune cells are B cells. B cells are like airport security dog handlers who come equipped with bows and arrows. They keep these arrows flying around in our blood circulation to defend our bodies from pathogens around the clock. Whenever you get a vaccine, you are training a special team of B cells to release their arrows and shoot down a particular pathogen so it cannot harm you. These arrows are called “antibodies.”

Antibodies are shaped like a “Y.” The two tips bind to their target. The base it can be grabbed by other cells so that they can collect and destroy the bound entity. So back in the airport, the dog (innate cell) smells a bad guy (for example, a tuberculosis bacterium) and barks, so the handler shoots the pathogen with arrows (antibodies), immobilizing the intruder. Then, the garbage-collecting cells called macrophages come by and haul the bad guy out by the protruding arrow shafts. Meanwhile, many other pathogens are getting shot down all across the airport by their own specially-trained B cells with their antibodies. It’s all a very tightly coordinated system.

Antibodies have proven to be exceptionally powerful tools in science and medicine because they can be designed to target almost any molecule.

The idea of using of antibodies for immunotherapy was sparked by innovation in cancer therapy. In 1997, rituximab became the first targeted antibody approved for the treatment of cancer.⁴ The molecule that rituximab recognizes is present on certain cancer cells; that is, by chance, cancerous B cells. It’s an intriguing coincidence that the very cells that can make antibodies were the first to be targeted with this approach. With the appropriate antibodies, other cancerous cell types can be targeted for removal, too.

Antibodies are extremely powerful tools, but it is important to know their limitations. In the case of rituximab, the antibody cannot distinguish between healthy or cancerous B cells, so all are destroyed, causing significant side effects. One recent improvement in antibody immunotherapy is the use of a bi-specific tip. In this approach, each of the two tips of the “Y” targets a different molecule on the B cell. By requiring two markers for an antibody to target a cell, we might be able to improve our ability to distinguish healthy and cancerous cells, thereby avoiding significant side effects.

Antibodies Across the Animal Kingdom

The evolution of the adaptive immune system has led to interesting differences in antibody structure and function across the animal kingdom. Humans and mice both produce the typical “Y” structure. But three animals have uniquely-structured antibodies: cows, camels, and sharks.

Cows have a typical Y-shape base, but each tip that is responsible for binding to the target is elongated. These extensions allow the cow antibodies to grip onto some proteins that a human or mouse antibody could not strongly bind. Scientists use these when they’re searching for a specific protein using a human or mouse antibody and need to block all of the other proteins in their sample from getting bound, to prevent a false alarm.

Camels, along with alpacas and llamas, have a basic Y-shape antibody structure, yet they lack the usual complexities associated with the targeting tips. The tips of camel antibodies are stunted and consist of about 80% less protein material than a typical antibody, ultimately leading researchers to coin the term “nanobodies.” Nanobodies are much less bulky and may allow researchers to target molecules that were previously inaccessible using typical antibody approaches.

Shark antibodies are similar to those of camels and llamas, but they have an extended base. The extended antibody base may help macrophages collect the identified target. These two features of an extended base coupled with miniaturized binding tips provide shark antibodies with a truly unique structure that could be used in novel medical technologies.

While biomedical researchers undoubtedly focus on human health, animals other than homo sapiens fight against the same fundamental diseases that we do. Understanding the unique differences in antibody shape and function across the animal kingdom — from sharks to llamas, and beyond — can inspire us to discover innovative new ways to fight cancer and other diseases. Rather than derive completely new technologies to fight disease, we can simply look to nature and copy what works well from other species.

The last 100 years of antibody research has paved the way for major breakthroughs in medicine around the world. The dawn of immunotherapy has arrived, and with it comes the potential for curing many diseases. Although there are many challenges ahead, the animal kingdom can be a great source for innovation.

The author working in the laboratory of Dr. Hubbell at the University of Chicago. The equipment shown here is used for liquid chromatography, which allows scientists to purify specific proteins, such as antibodies, from a mixture of cellular products. 

References

1. “A guide to cancer immunotherapy: from T cell basic science to clinical practice.” Alex D. Waldman, Jill M. Fritz & Michael J. Lenardo. Nature Reviews Immunology. 2020
2.  “Structural and genetic diversity in antibody repertoires from diverse species.” de los Rios, M., Criscitiello, M. F., & Smider, V. V. Current Opinion in Structural Biology. 2015
3. “Approaching the asymptote? Evolution and revolution in immunology.” CA Janeway. Cold Spring Harbor symposia on quantitative biology. 1989
4. “Using the Immune System in the Fight Against Cancer: Discovery of Rituximab”. NIH National Cancer Institute. 2014. <https://www.cancer.gov/research/progress/discovery/blood-cancer>