Scalable and adaptable, TETRIS captures the diversity of
protein interactions on site to inform accurate cancer diagnoses,
enabling the personalisation of ensuing treatments.
SINGAPORE, Sept. 30,
2024 /PRNewswire/ -- A team of researchers from
the National University of
Singapore's (NUS) Institute for Health Innovation
& Technology (iHealthtech), led by Associate Professor
Shao Huilin and Associate Professor Brian
Lim, has developed a first-of-its-kind technology to map out
diverse protein interactions in cells using DNA barcodes.
The technology, dubbed TETRIS, can explicitly identify and
quantify multiple interacting partners in large protein assemblies.
By capturing the complex hierarchy of protein interactions within
tumour cells, the technology uncovers detailed molecular mechanisms
driving disease progression. This enables more precise diagnostics,
allowing for the accurate sub-typing of cancers and the
identification of aggressive forms of the disease in just a few
hours, which was not possible previously.
Further, TETRIS provides vital insights from which doctors can
tailor therapeutic strategies to individual patients. For instance,
identifying the specific proteins and their interactions that
contribute to cancer growth can lead to targeted therapies that
improve patient outcomes.
The team's findings were published in the scientific journal
Nature Biomedical Engineering on 19 June 2024. The first authors of the study are
Dr Liu Yu and Dr Noah Sundah, both are research fellows from NUS
iHealthtech.
Unmasking insidious cancer cells
Proteins are responsible for nearly all basic processes of life.
Understanding how these building blocks of life interact with one
another is a critical facet of biology and medicine. Indeed,
proteins interact extensively with one another to drive important
functions and activities in health and disease – deciphering these
interactions can not only lead to better predictions of cell
behaviour, but also have wide-ranging clinical applications, from
improved disease diagnostics to developing more effective
therapeutic strategies.
Current methods for studying these interactions, however, have
limitations such as false results and incomplete profiling of
protein interactions, among others. The gold-standard approach —
yeast-two hybrid assays — requires genetic manipulation and is
limited to pairwise binary interactions, rendering it unsuitable
for clinical samples. Another common method — mass
spectrometry-based proteomics — often misses weak interactions due
to extensive sample processing and remains binary in its
evaluation.
All in all, these methods fall short of capturing the full
spectrum of protein interactions, particularly the higher-order
ones where multiple proteins interact to form large functional
assemblies; changes in higher-order protein interactions are often
linked to more aggressive types of cancer.
The NUS researchers turned to DNA nanotechnology for a solution.
"DNA is a programmable material and can be used to encode rich
information while having predictable interactions, which enables us
to craft sophisticated architectures with fine spatial control at
the nanometre scale," said Assoc Prof Shao, who led the design of
TETRIS. She is also from the Department of Biomedical Engineering
under the College of Design and Engineering at NUS.
Harnessing the advantages of DNA nanotechnology, TETRIS
leverages hybrid molecular structures as smart encoders to map
protein interactions directly in patient samples. Each encoder
carries a target-recognising antibody and a templated DNA barcode.
In action, the encoders not only bind to interacting proteins, but
also have their barcodes fused bilaterally with that of their
neighbouring units. The resultant barcodes thus capture all
information – molecular identity and spatial relationship – and can
be used to decode extensive protein interactions. Unlike current
methods, TETRIS measures both pairwise and higher-order protein
interactions, thereby providing a comprehensive picture of the
complex protein interactome.
"Think of proteins as delegates at a scientific conference. Each
delegate spots a name tag with a unique barcode. When they
interact, or 'shake hands', TETRIS captures these interactions by
linking their barcodes together. This creates a chain of
interactions that we can subsequently read and decode via
algorithms. Just like seeing who is chatting to whom at the
conference, TETRIS enables us to see how proteins interact within
cells, providing us with a lens through which we can understand and
diagnose diseases more effectively," said Assoc Prof Lim, who led
the development of algorithms used to process the data collected by
TETRIS. He is also from the Department of Computer
Science under the NUS School of Computing.
A standout feature of TETRIS lies in its ability to perform
on-site encoding and decoding of protein interactions directly in
clinical samples. The technology has been tested on biopsies of
human breast cancer tissues, from which it accurately diagnosed
cancer subtypes and revealed higher-order protein interactions
associated with cancer aggressiveness.
Transforming the future of healthcare
TETRIS provides a more detailed and accurate picture of the
molecular underpinnings of diseases — a boon for cancer diagnostics
and treatments. Changes in higher-order protein interactions, which
are hallmarks of aggressive cancers, can be more easily detected,
thus leading to more informed, personalised clinical decisions.
Additionally, TETRIS is designed with scalability and
adaptability in mind. The technology can process a large number of
samples and generate results quickly using existing laboratory
infrastructure — allowing it to be integrated into routine clinical
workflows with minimal disruption. For instance, the technology can
be used in a doctor's office, where samples obtained via
fine-needle aspiration — a safer and minimally-invasive biopsy —
can be rapidly analysed to inform treatment decisions.
The NUS researchers plan to expand the application of TETRIS to
other types of cancers and neurological diseases, potentially
paving the way for novel diagnostic tools and therapeutic
interventions across a broad spectrum of illnesses. The team has
filed two patents for the technology and hopes to commercialise the
innovation.
Read more at:
https://news.nus.edu.sg/revolutionary-technology-to-unravel-complex-protein-interactions
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SOURCE National University of
Singapore