Page 28 - Luce 2024

S tudent Voice

JCH post-graduate the ongoing development of cancer drug-resistance (Graph
student, Honglin 2). These challenges highlight the need for new generations
of therapeutics that are both highly specific and flexible, to
(Kevin) Chen, is design for precision personalised medicine.
studying a Ph.D. at
Switching the target from protein to DNA and RNA
the University of Intuitively, if proteins are too complex to target, we should
Melbourne with a focus look at their precursor DNAs and RNAs (Graph 1). Unlike
on cancer biochemistry proteins, these precursors are only made up of four simpler
building blocks (A, G, C, T for DNA; A, G, C, U for RNA)
and genetics. Kevin with less complex three-dimensional structures. Furthermore,
kindly agreed to share with us some of his insights recent breakthroughs in DNA sequencing and computational
technologies enable us to efficiently detect genetic aberrations
into the development of RNA-editing tools in
found in individual tumours. However, the ability to sequence
cancer research. the genome is not equivalent to the ability to modify them.
Altering DNAs and RNAs still seems distant and intangible
When Francis Crick coined the term ‘the central dogma’ in – although they are only made up of four simple bases, their
1958, the field of molecular biology was revolutionised. The seemingly random sequences create an infinite array of
vastly complex and seemingly convoluted cellular biology was functions. This makes it hard for scientists to target a specific
simplified and broken down into two crucial steps: RNA sequence without affecting a similar one.

1 DNA is first transcribed into messenger RNA; CRISPR to the rescue
2 Messenger RNA is then translated into protein by The breakthrough discovery of the CRISPR (Clustered
ribosomes (Graph 1). Regularly Interspaced Short Palindromic Repeats) and Cas
(CRISPR-associated protein) systems has revolutionised
Like Einstein’s Unified Field Theory, the central dogma biological sciences and holds immense potential for gene
elegantly demonstrated the striking uniformity of all biological editing technologies to rewrite the blueprint of life. The
organisms. At the very heart of the central dogma is the key emphasis here being the word ‘discovery’ rather than
messenger RNA, a crucial intermediate product that links ‘invention’ – we merely discovered the system in bacteria,
DNA and protein and is the key to all organisms’ survival. which functions as their adaptive immune system. A key
feature of a functioning immune system is the ability to
Cancer & current challenges differentiate foreign entities from the host. Failure to recognise
Cancer isn’t just a single condition but a result of a cellular foreign invaders will expose the host to infections, which can
circus gone haywire due to excessive genetic mutations. cause the invaders to take over the host machinery for their
Picture this: a genetic meltdown leading to abnormal proteins own replication and will often become fatal. Since bacteria
causing unchecked cell growth. As cancer is a disease that have been fighting against invaders like bacteriophage viruses
originates from ‘self’, there is a lack of ‘foreign’ targets that and other mobile genetic elements for millions of years, such
distinguish cancer cells from normal cells. Current first-line principle is as critical for bacteria, if not more, as for humans.
treatments heavily weigh on chemotherapy or radiotherapy, CRISPR/Cas system evolved as a nucleic acid-based (different
which induce cell death by causing massive unrepairable variants target either DNA or RNA) defence system.
mutations. However, these treatments work by killing cells
with fast metabolism – while effective, they are blunt tools CRISPR/Cas13 – an RNA-targeting system
that also cause massive collateral damage to healthy fast- There are numerous CRISPR/Cas systems individually evolved
dividing cells, leading to severe side effects in the patients. in different bacteria to target different viral targets. For my
research, I am focusing on CRISPR/Cas13, an RNA-targeting
Enter the cavalry: small-targeted drugs that zero in on specific CRISPR system. When an RNA virus infiltrates a bacterial host,
rogue proteins within cancer pathways, which solves the issue a cascade of events is triggered: the Cas13 protein and the
of non-specific cell killing as only cancer cells with aberrant CRISPR locus spring into action (Graph 3). This orchestrated
proteins are targeted. Sounds promising, right? But here’s response leads to the generation of Cas13 effector proteins
the catch – cancer cells are crafty and can quickly develop and crRNA molecules that align with specific segments of the
resistance to these drugs, rendering them less effective over viral RNA sequence. When the target is found and sequence
time. Plus, targeted drugs take up a huge amount of time to matching occurs, the Cas13 protein undergoes a shape change
develop due to the complexity of protein structure. There is to expose its endonuclease domain, thus cleaving the target
a very limited number of drugs available for known tumour RNA.
driver proteins, which also makes it hard to keep up with

28 LUCE Number 22 2023