Bowhead whales have given scientists a hope of curing one of the most devastating diseases that affects humans and other animals. Cancer occurs when cells in the body grow uncontrollably and form tumors that can damage vital organs and tissues. The risk of developing cancer increases with age, exposure to carcinogens, and genetic factors. However, some animals seem to have a natural resistance to cancer, despite having many more cells than humans and living much longer. One of these animals is the bowhead whale, the world’s longest-lived mammal.
Bowhead Whales Have Remarkable Longevity and Low Cancer Rates
Bowhead whales (Balaena mysticetus) can live for over 200 years and weigh up to 80 tons. According to Peto’s paradox, a phenomenon named after the British statistician Richard Peto, large and long-lived animals should have a higher chance of getting cancer than smaller and shorter-lived ones, because they have more opportunities for mutations to occur in their DNA. However, this is not what scientists have observed.
Bowheads have very low rates of cancer, suggesting that they have evolved some mechanisms to prevent or repair DNA damage that could lead to tumors. Their exceptional longevity has intrigued scientists and sparked investigations into the underlying mechanisms that enable these marine giants to live such extended lives without succumbing to age-related diseases, including cancer.
Investigating the unique biological adaptations of these marine mammals can provide valuable insights into the mechanisms that underlie cancer resistance.
Ability to Repair DNA Damage
Bowhead whales may resist cancer thanks to their superior DNA repair ability. The cells of bowhead whales seem to be better at repairing DNA than other species, which is why they live hundreds of years without cancer. They have unique mutations in a gene called ERCC1. It allows them to fix DNA damage effectively and maintain the stability of their genome.
In normal cellular processes, DNA damage can occur due to various internal and external factors. DNA, the genetic material of cells, is constantly exposed to potentially damaging agents such as reactive oxygen species, ultraviolet (UV) radiation, chemical carcinogens, and errors during DNA replication. DNA damage can lead to disruptions in the genetic code, impairing normal cellular function and potentially promoting the development of diseases, including cancer.
To maintain genomic integrity, cells have evolved sophisticated DNA repair mechanisms that detect and rectify various types of DNA damage. These repair processes are crucial for the preservation of DNA structure and function, preventing the accumulation of mutations and chromosomal abnormalities that could drive cancer initiation and progression.
Common types of DNA Damage and Repair Pathways
The DNA repair mechanisms function through a series of steps involving recognition of damaged DNA, removal of damaged or incorrect nucleotides, and subsequent synthesis and ligation to restore the original DNA sequence. These repair processes are tightly regulated and coordinated to ensure accurate and efficient repair of the lesions. However, despite the robust mechanisms, errors can still occur, leading to the buildup of DNA damage. When repair attempts fail to adequately restore the DNA structure, persistent damage can contribute to genomic instability and increase the risk of cancer development.
Therefore, different types of DNA damage require specific repair pathways for effective restoration. These pathways are intricate and highly regulated systems that safeguard the integrity of the genetic material by detecting and repairing DNA damage. Here are some common types of DNA damage and their repair pathways.
Single-Strand DNA Breaks
Single-strand breaks occur when one of the two strands of the DNA double helix is severed. They can result from oxidative damage or exposure to ionizing radiation. Repair pathways such as base excision repair (BER) and nucleotide excision repair (NER) are responsible for detecting and correcting single-strand DNA breaks.
BER primarily repairs DNA damage that involves modifications or small lesions in individual bases of the DNA molecule. It is involved in the repair of DNA base modifications caused by oxidative damage, spontaneous hydrolysis, or exposure to certain chemicals. BER involves a series of sequential steps, including the recognition and removal of the damaged base by specific DNA glycosylases, followed by the excision of the resulting abasic site and subsequent DNA synthesis and ligation to restore the original DNA sequence.
On the other hand, NER is responsible for removing bulky DNA lesions that distort the DNA helix, such as those induced by UV radiation or chemical carcinogens. NER operates through a complex series of steps, including lesion recognition, incision on both sides of the lesion, excision of the damaged DNA segment, and DNA resynthesis and ligation to restore the DNA structure. NER can effectively repair a wide range of DNA lesions and plays a critical role in maintaining genome integrity.
Double-Strand DNA Breaks
Double-strand breaks (DSBs) are severe types of DNA damage where both strands of the DNA molecule are broken. Two main pathways are involved in repairing DSBs; homologous recombination (HR) and non-homologous end joining (NHEJ).
HR repairs DSBs during the S and G2 phases of the cell cycle. It utilizes an undamaged sister chromatid or homologous DNA sequence as a template to accurately restore the DNA sequence at the break site. It involves a series of steps, including DNA end resection, homology search and strand invasion, DNA synthesis, branch migration, and resolution, resulting in the repair of the DSB.
NHEJ is an error-prone but rapid DNA repair pathway that operates throughout the cell cycle to repair DSBs. NHEJ directly ligates the broken DNA ends without requiring extensive sequence homology, making it a versatile repair mechanism. However, due to its error-prone nature, NHEJ can lead to small insertions or deletions at the repair junction, potentially causing mutations. NHEJ is critical for repairing DSBs, particularly in non-dividing cells or when homologous templates are not readily available.
DNA Mismatch
DNA replication errors or the presence of mismatched nucleotides can result in DNA mismatches. Mismatch repair (MMR) is a specialized repair mechanism that recognizes and corrects these mismatches, ensuring the fidelity of DNA replication. It is highly accurate in correcting errors that arise during DNA replication, such as mismatched nucleotides or small insertion-deletion loops. MMR relies on the detection of mismatches by specific proteins, followed by the excision of the wrongly-paired segment and subsequent DNA resynthesis and ligation. MMR is essential for maintaining genomic stability and preventing the accumulation of replication errors that can lead to mutations and cancer development.
Comparative Genomics
Comparative genomics is the study of the similarities and differences in the DNA sequences of different species. By comparing the genomes of bowhead whales and humans, researchers can identify genes that are under positive or negative selection, meaning that they have changed more or less than expected by chance. These genes may be involved in important biological processes like aging and cancer.
A study published in Nature Reviews Cancer sequenced and compared the bowhead whale genome and two transcriptomes (the set of all RNA molecules in a cell) from different populations found several genes that were under positive selection or had bowhead whale-specific changes in gene expression. Some of these genes were related to cancer and aging, such as genes involved in DNA repair, cell cycle regulation, apoptosis (programmed cell death), and insulin signaling.
For example, one gene was BRCA1, which is well known for its role in breast and ovarian cancer in humans. Mutations in BRCA1 impair its ability to repair DNA damage and increase the risk of cancer. However, bowhead whales had a unique mutation in BRCA1 which enhances its repair function.
Cell cycle regulation is another important process for controlling cell growth and division. One of these genes was CCND1, which encodes a protein called cyclin D1 that promotes cell proliferation. Overexpression of CCND1 is one of the main cause of human cancers. However, bowhead whales had a mutation in CCND1 which reduces the proliferation activity.
Similarly, several other gene processes work differently in bowheads and humans. The giant mammals have evolved multiple molecular adaptations, thus, expanding their lifespan. Researchers seek to harness this molecular evolution to discover novel targets for cancer prevention or treatment in humans.
Potential Applications for Human Cancer Treatment
The exceptional biology of bowhead whales may offer valuable clues for improving human health on a larger scale than curing cancer. The enhanced DNA repair ability of bowhead whales may explain how they avoid cancer and achieve longevity. It may also provide insights for developing new strategies for human cancer prevention and treatment. For example, drugs that mimic or enhance the function of DNA repair proteins could potentially improve the outcome of cancer patients. Alternatively, studying the genetic variations that underlie the DNA repair ability of bowhead whales could help identify new targets for cancer therapy.
However, further studies are required to translate these findings into practice. There are still many challenges and limitations to applying the knowledge gained from the whales to human cancer research. For one thing, bowhead whales are endangered species and are difficult to study in their natural habitat. Moreover, there may be other factors besides DNA repair that contribute to their cancer resistance and longevity, such as immune system function, metabolism, or gene expression regulation. Therefore, more research is needed to fully understand the molecular mechanisms and evolutionary origins of this creature’s fascinating traits.
