Bioluminescence - the emission of light by an organism - is amongst nature’s most charming phenomena. A new phototherapy, which uses light emission from fireflies, aims at stimulating the self-destruction of remote tumours. Could this illuminate the path to a cancer-free future? By Calista Chan
Presenting itself in larvae, deep-sea critters - and most famously, the firefly - bioluminescence has long played a vital role in creature survival, providing a means for hunting, fleeing and mating (Bioluminescence, 2023). Light emission is thought to occur as a result of luciferin oxidation by its corresponding enzyme luciferase (Fireflies and Firefly Bioluminescence, 2017). Now, scientists are exploiting this reaction in a bold venture to transform our approach to modern cancer treatment.
Figure 1: Firefly light emission is thought to be a product of luciferin-luciferase reactions. It is initiated when enzyme luciferase binds to substrate D-luciferin in the presence of ATP and Mg2+, catalyzing its oxidation with molecular oxygen. As a result, oxyluciferin is formed in its high-energy, unstable state. Afterwards, oxyluciferin quickly loses energy, decaying to its low-energy, stable state and emitting light in the process (Fireflies and Firefly Bioluminescence, 2017). (Note that luciferase can be recycled and will continue to catalyze the above reaction so long as luciferin and O2 are present.) Image from Ripp and Sayler (2011).
Endogenous light emission by luciferin reactions was first investigated in 2003 by the Ludwig Institute of Cancer Research at UCL, in which NIH 3T3 murine fibroblasts - a type of connective tissue in mice - was modified to express the firefly luciferase gene in vitro (Theodossiou, 2003). Ever since, researchers have been examining the efficacy of firefly luciferin reactions in light-based cancer therapy (i.e. phototherapy). Ultimately, this has given rise to what is known as Bioluminescence-Mediated Photodynamic Therapy (bPDT) - an innovative phototherapy that fuses the firefly luciferin-luciferase reaction with photodynamic therapy (Ng et al., 2022).
Figure 2: Photodynamic therapy (PDT) is a phototherapy involving the use of a photosensitizer and external light source. The photosensitizer, applied topically or intravenously, is highly selective to tumor cells. Upon exposition to an external light source, the photosensitizer fluoresces, transferring energy to molecular oxygen. This enables the accumulation of reactive oxygen species in the cell, leading to apoptosis (Correia et al., 2021). Image author unknown (Red Laser Diodes for Photodynamic Therapy, 2019).
bPDT poses a vital question. What are the benefits of integrating luciferin reactions with PDT? To grasp this, it is crucial to understand the shortcomings of PDT stand alone. While the minimally invasive, high-precision nature of PDT has posed a significant advantage in cancer therapy, one of PDT’s most defining limitations lies in its scope (Correia et al., 2021; Ng et al., 2022; Theodossiou et al., 2003). Indeed, PDT is only effective on highly accessible tumors located on or near the surface of the skin, as well as in hollow organs (i.e. the lungs); ultimately, restricting treatment on deep, remote tumors inaccessible without surgical intervention (Correia et al., 2021).
Figure 3: While the external light source is usually unable to penetrate beyond a few millimeters into the skin; strictly speaking, it is possible for a light source to reach a deep-lying, remote malignancy through a minimally invasive surgical means. That being said, light distribution over the tumor is neither uniform or homogenous in this technique, rendering PDT ineffective (Theodossiou et al., 2003). Likewise, in the case of a diffuse metastatic tumor, delivering an exogenous light source would also pose significant challenges (Ng et al., 2022). Image author unknown (Laparoscopy, 2014).
Indeed, while bPDT adopts the same basic principle as PDT, they differentiate in their light sources. While PDT applies an external light source to trigger photosensitizer fluorescence and molecular oxygen breakdown, bPDT derives light intrinsically - or in scientific terms, endogenously. Put simply, this means that the deep-lying, isolated malignancies act as their own light source; ultimately, facilitating the simultaneous self-destruction of the remote tumor (Ng et al., 2022, Theodossiou et al., 2003).
Unlike larvae, the firefly and other distinct light-emitting species, humans - like all mammalian cells - do not synthesize natural luciferase. As a result, most research on bPDT thus far centralizes on the transfection of the luciferase gene into malignant tumors. A study of this kind was conducted recently at the UCL Institute of Neurology, wherein grade 4 astrocytoma - a common malignant tumor in the glial cells of the central nervous system - was genetically modified to express the firefly, beetle and Renilla luciferase gene in vitro. Results of the study were promising, revealing firefly-transfected glioma - all of which expressing the luciferase gene - illustrated a high rate of cytotoxicity upon exposition to D-luciferin and a photosensitizer (Ng et al., 2022).
Naturally, the emergence of bPDT as a viable phototherapy has raised key questions about the implications of this technology. While work on bPDT has been promising, it is a relatively new technology; our understanding is still - to some extent - in the rudimentary stages, making it difficult to fully grasp its scope (Ng et al., 2022). In spite of this, bPDT has shown optimistic results in becoming a practical extension of existing phototherapies. With further research, there is every reason to believe bPDT will be a strong asset in our path to achieving a cancer-free future.
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Cover Image: https://www.pexels.com/photo/fire-particles-floating-through-the-green-fern-leaves-9007628/
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