Throughout the world there are thousands of species with wonderfully unique abilities. For humans, this leaves much to desire: such as geckos’ self-regenerating limbs, or reindeer’s colour-changing eyes as they adjust to dark winters. The rich diversity of the natural world can teach us so much, and is constantly being used to further the fields of medicine and technology. One class of vertebrates in particular has been pivotal in the world of immunology and cancer biology - sharks.
As some of the oldest living vertebrates to possess antibodies, sharks’ immune systems have been refined for over 450 million years, resulting in a remarkably high resistance to disease. For the most part, sharks’ immune systems function similarly to humans’, with the use of antibodies to deliver specialised defence against pathogens. However, there are unique mechanisms within shark immune systems, preserved from ancient ancestors, that set them apart from humans.
In particular, sharks are thought to have the lowest incidence of tumours or cancers of any vertebrate group. This has piqued the interest of researchers as it suggests sharks have evolved superior genes and mechanisms to protect themselves from cancer. Research into these features of the shark immune system, and how they differ from humans, is providing a cause for hope in the development of cancer therapeutics.
The secret to sharks’ impressive immunity lies in their genetic code. Several immunologically important genes have been identified in the shark genome that are modified compared to their mammalian counterparts. For example, Bag1 and Legumain genes, which both have important roles in the healthy function of the immune system, were found to have novel adaptations in sharks.
Bag1 is a key gene in regulating and stopping programmed cell death. As cancer cells are often able to evade cell death, Bag1 has been highlighted as an important gene in aiding tumour growth. While it is not yet known exactly how the function of Bag1 is altered by these adaptations, it has been proposed that Bag1 in sharks has a modified role in programmed cell death, one which reduces its tendency to inhibit the process. These findings support the existing theory that sharks have evolved enhanced anti-tumour abilities through suppressing the activity of genes like Bag1 that regulate programmed cell death.
Legumain plays a key role in the activation of an immune response against a pathogen in both humans and sharks. Legumain in humans has been found to be hyperactive in several cancers, leading to tumour progression and tissue deterioration. In sharks, Legumain’s adaptations have likely altered its role, changing how it functions in the immune response and in tumour development. More research is required to truly understand the novel function of Legumain in sharks, but this knowledge of how sharks have adapted to reduce their cancer risk could be extremely valuable in the development of cancer research.
In 2019, the genome of the ocean’s most formidable predator, the great white shark, was sequenced in its entirety, which means that all of its DNA has been mapped out, allowing for gene analysis. This led to exciting revelations surrounding their resistance to disease. It was found that great white sharks possess several modified genes, most notably those that play a role in maintaining genome stability. Genome instability is largely a result of DNA damage accumulated over time, and is one of the most common predispositions to cancers and age-related diseases. Great white sharks appear to have overcome genome instability by modifying genes to promote DNA repair, thus reducing their risk to cancer.
Whale sharks, the largest fish in the ocean, were found to share these gene adaptations. Generally, an individual’s risk of cancer increases with their body size. Due to the size of great white sharks and whale sharks, it is thought that sharks originally did have a larger risk of cancer, which acted as a pressure on natural selection, and drove the evolution of superior protective abilities against cancer.
These discoveries have provided promising insight into how sharks are so adept at preventing cancer, and led to research into the genetic engineering of shark genes to aid in cancer therapeutics and tumour detection.
There is one particular element of the shark’s immune system that has already proven to have significant potential in the field of cancer biology - the variable new antigen receptor, or VNAR. VNAR is a type of protein that binds to antigens, which are distinctive protein tags found on foreign cells or toxins. VNAR blocks their function, preventing them from causing disease. It has a unique structure, with rearranging abilities, making it highly variable and able to target many different pathogens. When studied in nurse sharks, the gene encoding VNAR was found to have high levels of diversity between individual sharks. This indicates an ability to mutate in response to the introduction of new pathogens and provide targeted responses.
VNAR’s rearranging abilities make it ideal for targeted treatments, as it can be engineered to recognise any target, whether it be a virus, bacteria, or cancer cell. Another feature of VNAR that makes it a suitable molecule for cancer treatment is that it is exceptionally small, and therefore able to access tumour cells in complex environments such as bone.
Dr Aaron LeBeau, of the University of Wisconsin-Madison Carbone Cancer Center, has been pioneering the development of using VNAR for nuclear imaging to accurately detect metastatic cancer, and to monitor for disease recurrence. Metastatic cancer refers to cancer that has spread from the original tumour to other parts of the body, and secondary tumours have formed - it is incredibly difficult to treat and clear cancer at this stage. The ability to monitor for tumour recurrence could be hugely influential in preventing metastatic cancer and allow for targeted treatment against tumours.
VNAR has already proven to be effective in treatment of Covid-19, and it is showing potential for use in cancer therapeutics, as well as detection and prevention. It was investigated as a potential for anti-tumour therapies based on its unique structure and abilities that current anti-tumour drugs lack. A VNAR variant was combined with an anti-tumour drug to form a new recombinant drug. This has the potential to successfully target and clear tumours at an early stage, preventing severe cancer, and is a non-invasive alternative to other difficult cancer therapies.
These novel shark genes have shown great promise in the world of cancer biology and could provide new methods of detection, prevention and treatment. Research into VNARs could be ready for clinical trials within the next few years. The potential found in these animals sheds light on just how important protecting the diversity of the natural world is, as it rapidly declines across the globe. Many species of sharks, among countless other organisms, are threatened, disappearing before we fully understand them. Now more than ever, it is vital to protect the natural world, before unique and valuable species are lost forever.
