Therapeutic proteins are proteins that
are directly injected and used to restore
a diseased status to normal. These
proteins can provide a missing activity
or can attenuate an excess activity, in
either case bring the system back to a
more homeostatic state.
Prof Mingjie Zhang, IAS Senior Fellow and Kerry
Holdings Professor of Science (middle) and the IAS
HKUST-Scripps researchers (from left: Feng Wang,
Carol Lau, Zhiwen Xu and Cario Lo)
The past and future of therapeutic
proteins
One of the earliest and widely-applied
therapeutic proteins is insulin for
treating Type 1 diabetes mellitus.
Another is erythropoietin (also known as
EPO), a natural protein that stimulates
growth of red blood cells, especially in
people undergoing kidney dialysis or
others who are anemic. Nowadays,
more than 100 of therapeutic proteins
are approved for clinical use in the
European Union and the US with Year
2010 sales of US$108 billion.
Scientists on one hand search for
potential therapeutic proteins or their
targets by investigating mechanisms of
disease pathologies, and on the other
hand develop technology to modify
therapeutic proteins for enhancing their
treatment effects and research new
delivery strategy to safely and
efficiently apply the proteins. At the
moment, one of the variants has been
tested in animal models for
inflammatory conditions for which little
are available to treat. Human clinical
trials are being initiated.
Recent research by IAS HKUST -
Scripps R&D Lab
We established a systematic
methodology for discovery of novel
naturally-occurring splice variants and
characterization of their biological
activities. Splice variants are novel
versions of known proteins that have
been reorganized into new structures
with new activities. We found that, by
analogy, each discovered variant is like
a caterpillar being turned into a
butterfly — a whole new shape and
function that you could not have imagined.
Prof Paul Schimmel, IAS Visiting Professor and Ernest
and Jean Hahn Professor of Molecular Biology and
Chemistry in The Scripps Research Institute (TSRI)
The existence of most of these new
splice variants was unknown at the time
the Laboratory initiated its
investigations. We applied this
methodology to the aminoacyl tRNA
synthetases (AARS) and identified more
than 250 new proteins that potentially
can serve as therapeutic proteins. In
principle, this analysis can be applied to
any known genes for identification of
more potential therapeutic proteins.
In our platform, we developed an AARS
transcriptome enrichment method and
used high throughput deep sequencing
to comprehensively identify new AARS
variants. With deep sequencing we
identified billions of bits of information
about the variants. The project thus was
highly dependent on sophisticated and
powerful computing analysis, to sort
out and interpret that data. In short, the
work was an example of what is called
today a 'big data' project. We then
studied the AARS variants in the
context of expression and distribution
across various human tissues, and at
different developmental stages (for
example, fetal versus adult brain tissue).
We also expressed the variants and
examined potential biological activities
in a diverse set of cell-based assays.
Here again, 'big data' came into play,
as we gathered over 100,000 data
points and had to interpret all of them.
Importantly, we found most variants
had highly specific novel activities,
which were idiosyncratic to the variant.
The implication is that many diseases
could be impacted by these
discoveries.
Working concertedly for six years, the research team of IAS HKUST-Scripps R&D
Laboratory led by Prof Paul Schimmel, IAS Visiting Professor and Ernest and
Jean Hahn Professor of Molecular Biology and Chemistry at TSRI (California and
Florida), has discovered 250 new proteins with previously unidentified activities.
Such findings highlight an intriguing oddity of protein evolution as well as a
potentially valuable new class of therapeutic proteins. The findings are published
in
Science
in July 2014 with Prof Mingjie Zhang, IAS Senior Fellow and Kerry
Holdings Professor of Science, Division of Life Science at HKUST as one of the
co-authors of the report.
Variants produced only in specific cells
The research concerns aminoacyl tRNA synthetases (AARS), a group of 20 enzymes
which connects the nucleotide codes contained in genes to their corresponding
protein building-blocks, the 20 amino acids. By using advanced and sensitive
techniques, the team collaborated with colleagues at TSRI in California and Florida
and the biotech company aTyr Pharma has identified nearly 250 previously unknown
gene-transcript variants of AARS in different human cell types. These variants, known
as splice variants, are alternative assemblies of the discrete sequences of information
contained in AARS genes. The team also revealed that the new AARS variants are
often produced only in specific cell types such as brain or immune cells, and/or appear
only during certain stages of development. Moreover, with the discovery on lacking
“catalytic domain” for protein translation, it hinted at a diversity of the function of
these variants. One variant for analysis is found to be a powerful driver for the
proliferation of muscle fiber cells in a laboratory dish.
Breakthrough on protein therapeutics
As injectable proteins are displacing traditional chemical-based drugs, the finding of
these enzymes represents a very important class of new protein therapeutics
analogous to widely used injectable protein therapeutics such as growth hormone and
insulin. The team and the collaborators will continue their hard work on more
comprehensive studies of the new AARS variants and their specific functions.
IAS-Scripps
Scientists Discover
250 New Proteins
The Exploration of
Therapeutic Proteins
By IAS HKUST - Scripps R&D Lab
The new findings on AARS have been published on Science in July 2014. For more details on the influence, please read to “IAS-Scripps Scientists
Discover 250 New Proteins” on P.7.
Knowledge Corner
IAS Community
Sep 2014
Sep 2014
7
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