The Multi-omics revolution · The Multi-omics revolution By Deborah Grainger Ph.D c urrently,...
Transcript of The Multi-omics revolution · The Multi-omics revolution By Deborah Grainger Ph.D c urrently,...
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The Multi-omics revolutionBy Deborah Grainger Ph.D
c urrently, genomics studies contribute the vast majority of precision medicine- based data. As of August 2016, over 2,500 genome wide association studies (GWAS) have published their findings in the literature 1. And this figure is set to rise as improvements in next generation sequencing (NGS) technologies continue to reduce the cost and turnaround time per genome sequenced. Add to this the parallel leaps and bounds being made in bioinformatics and computational capacity and one essentially has the blueprints for a genomic golden era, which can only mean good things for precision medicine. However, although genomics big data offers a pretty comprehensive snapshot of what precision medicine entails at present, the discipline is set to encompasses much, much more than DNA-based data.
Underneath the buzz and excitement generated by genomics data, and the valuable ground being gained with them, there are other engines at work in
the field. These represent a largely unheralded revolution taking place; one which, despite the lack of fanfare, is poised to change the shape of precision
medicine for good. But rather than a revolution borne of one discipline in particular, it is in fact the combination of several: it is proteomic, lipidomic
and it is metabolomic too. It’s a charge that rallies multiple omics, or multi-omics, to its cause; it is a call for unison…and diversification.
Biomarker discovery
Those heeding this call are scientists like Tony Whetton, one of the masterminds behind the recently opened Stoller Biomarker Discovery Center at
the University of Manchester. The Center is set to “develop an ecosystem” for biomarker discovery in the context of precision medicine. Moreover, it is
poised to do this using a multi-omics approach; “In terms of the search for biomarkers, we’re not only talking about a search for genomic markers, but
protein, metabolites and, potentially, lipid-based biomarkers too.” Whetton, a professor of cancer cell biology, who has worked in the field of leukemia
research for over 30 years, is clear on the direction The Stoller will take, “A multi-omics approach to precision medicine is vital.”
Working alongside The Stoller’s scientists is the biotechnology company SCIEX, a world leader in mass spectrometry (a term often shortened to ‘mass
spec’). SCIEX has provided The Stoller with thirteen high throughput (HTP) mass spectrometry platforms, which are being used to process hundreds of
patient protein samples per run. Aaron Hudson, Senior and General Manager of SCIEX Diagnostics, who has also been involved in The Stoller project
since its early conception, was also involved in the decision to take a multi-omics approach; he commented, “Much of the precision medicine that is
being done [at The Stoller], and at other centers around the world, is now looking beyond genomics. It’s not enough just to look at DNA and RNA
anymore; you’ve got to look at the way the whole body is interacting. You have to expand into proteins, lipids and metabolites.”
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Up until recently, it has been very difficult to
perform the level of HTP screening required
by precision medicine-based approaches with
mass spec instruments, but SCIEX has done a lot
to improve capacity and data processing in this
area. One of the developments that has dras-
tically increased the amount of data obtained
per mass spec run is the company’s proprietary
SWATH analysis technology. Said Hudson of the
platform, “SWATH enables the quantification
of up to 5,000 proteins across hundreds of
samples, and does it reproducibly.” Without this
reproducibility, analyzing mass spec data is akin
to “looking for a needle in a haystack,” he added.
SCIEX has also developed a similar solution
for lipidomics as well: “We’ve now launched a
platform that can quantify 1,300 lipid species
in about 20 minutes in hundreds of samples.”
Hudson confirmed. SCIEX is so committed to
bringing multi-omics data processing up to
speed that it has recently partnered with NGS
experts Illumina to bring SWATH computing to
more users via a cloud solution called OneOmics.
Whilst these advances in sample processing
and data handling have moved things forward
considerably in terms of protein and lipid
analysis, Hudson admits these still have some
way to go before they are at the same stage as
genomic sequencing. Niven Narain, CEO and
Co-Founder of BERG Health, a company that
develops precision therapeutics using its
own multi-omics-based solutions, holds a
similar view on the current progress being
made with multi-omics approaches. In 2008
BERG launched its Interrogative Biology®
platform, which brought one of the first
multi-omics solutions to the market, but
Narain is concerned that not enough have
followed in BERG’s footsteps, “I would argue
that after eight years, multi-omics needs are still
not being met. If you mention ‘lipidomics’ or
‘metabolomics’ to people, sure, they’ve heard
those terms and there may be several related
projects out there, but how many big pharma
companies are involved?”
Unexpected Results
For BERG the progression to multi-omics was
a simple philosophical matter as Narain
explained, “Before we make decisions as
doctors and scientists, we need to learn as
much as we can about the entire biological
narrative.” He then went onto describe how
the Interrogative Biology® platform uses
artificial intelligence (AI) to drive hypothesis
-free therapeutic discovery. To do this BERG
collects hundreds, if not thousands, of healthy
and diseased samples and, in addition to
genomic information, obtains proteome,
lipidome and metabolome data from them
as well as information on mitochondrial
function, oxidative states, and ATP production
(a read-out of cellular energy levels). This
unstructured, big data is then processed by
the AI built into the Interrogative Biology®
platform, “What we’re doing is asking the
biology, not just the genes, what has gone
wrong in the disease state, and what can be
done to fix it.”
Narain cautioned that this approach may throw
out a few surprises; take one of the diabetes
drugs in BERG’s research and development
pipeline for example. When AI algorithms
identified an enzyme called enolase as a
potential drug target for diabetes, a lot of head
scratching was done. Here was data pointing to
an intermediary enzyme sitting in the middle
of a metabolic pathway. “We had our doubts,
but we couldn’t build this amazing platform
and be biased, so we carried on and now the
drug is validated at the preclinical stage.” The
drug’s mechanism of action has since been
shown to increase glucose transporting proteins
GLUT2 and GLUT4 in skeletal muscle and hence
increase glucose disposal to this tissue from
the bloodstream. “So the multi-omics approach
really works, it can be done,” Narain concluded.
Living Multi-omics
Also advocating the multi-omics route is
Helomics™ President and CEO Neil Campbell,
whose résumé also includes time as Senior
Director of Commercial Development at Celera
Genomics, a key industry partner in the Human
Genome Project (HGP). “NGS is a ‘hot’ area and
it’s what you always hear about, but you never
hear about proteomics in a broad way; you
never hear about tumor biology either, because
people are reluctant to work with live, fresh
tissues.” Helomics™’ unique contribution to
the multi-omics sphere involves working with
such tissues. Its Precision Cellular Analytical
Platform (PCAP™) maintains tumor samples
outside of the body, as ‘virtual patients’. Rather
than providing a snapshot of a tumor as fixed
samples do, the platform is able to capture a
‘feature-length’ movie of tumors as they grow
and change in real-time. This approach
maintains the individuality of each tumor
sample and allows Helomics™ to perform full,
comprehensive tumor profiling and reliably
interrogate tumor vulnerability with different
classes of drugs, sparing the patient unnecessary,
grueling trials of different drug regimens.
PCAP™’s live cell tumor profiling capabilities
also highlight why a multi-omics strategy is
superior to one solely based on genomics.
“There are driver mutations and passenger
mutations that are, respectively, either more
active or passive in a disease state. You might
be a breast cancer patient whom genomic
sequencing has identified as a BRCA1 or 2 gene
mutation carrier, but the real question is: is
your mutation transcribing and causing change
to proteins downstream?” Campbell explained
further, “If the answer to that question is yes,
you have a driver mutation and need to be
treated accordingly. But if it’s no, and it’s a
passenger mutation, literally just sitting along
for the ride, your physician needs to take this
into consideration when identifying the best
treatment for you.” Multi-omics approaches
can differentiate between patients in this way
as they take proteins into consideration too,
an area where Helomics™’ PCAP™ technology
excels as it monitors protein-protein interac-
tions anywhere in the cell, as they’re happening.
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Image supplied courtesy of SCIEX. © 2016 AB SCIEX.
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Future Directions
As new multi-omics programs such as The
Stoller Biomarker Discovery Center’s begin to
reveal new biomarker data, and as companies
like BERG Health and Helomics™ continue
to see ‘theranostic’ success with their multi-
omics platforms, we may begin to see more
multi-omics strategies become available as
more innovation takes place in the field.
Yet for Emmanuel Petricoin, the Co-Director
of the Center for Applied Proteomics and
Molecular Medicine (CAPMM) at George
Mason University, it is not a lack of upcoming
technology and industry involvement hindering
the uptake of multi-omics solutions; rather, it
is due to a lack of access. Said Petricoin: “The
vast majority of all cancers in the US are treated
at the community level; these patients are not
going to the MD Andersons or the Memorial
Sloan Ketterings of the world to be seen,
they’re being treated out in the community.
As molecular profiling ‘technologies’ both
proteomic and ‘genomic’ are becoming more
‘commoditized’ more patients are now getting
access to them than if they were solely avail-
able at the top-flight cancer centers; however,
there’s still no infrastructure out in the com-
munity for patients to access them routinely.”
In Petricoin’s view what’s needed isn’t more
new multi-omics technologies per se, but a
third-party to oversee them. A precision
medicine ‘orchestra conductor’ or ‘traffic
control cop’ that coordinates the whole
process from start to finish. He rationalised,
“Coordinating with pathologists and interven-
tional radiologists and surgeons, arranging
biopsies, figuring out which multi-omics
companies to send tissue to, then collating and
aggregating all the results and then relating that
data to the most up-to-date science, is difficult
even for one patient and it’s likely to only be
done on a one-off basis. Laying all that into a
real workflow for every cancer patient no matter
where they live, is what needs to be done.”
This is the space Perthera, a company Petricoin
cofounded, aims to occupy, revolutionizing
patient access to multi-omics technologies by
orchestrating the entire precision medicine
process for them. Perthera doesn’t practice
medicine or treat the patient, but acts on their
and their physician’s behalf, with their express
permission, to acquire the patient’s tissue from
the pathology lab or schedule a biopsy with
interventional radiology. Perthera then sends
samples of this tissue to a host of different
CLIA/CAP accredited labs it has handpicked
to perform genomic, proteomic and phosphop-
roteomic genomic and proteomic analyses, and
will soon be “layering on an RNASeq transcrip-
tomic analysis.”
Advertising Index
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Affymetrix, Inc Page 4
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Bio-Rad Laboratories, Inc Page 14
Canon BioMedical, Inc Page 56, 68
Helomics, Inc Page 84
Illumina Page 36
Intermountain Healthcare Page 29
Nanthealth Page 47
N of One, Inc Page 60
Oracle Page 33
Perthera Page 80
Silicon Biosystems S.p.A Page 10
SeraCare Life Sciences Inc Page IFC
Somalogic, Inc Page 6
Trovagene, Inc Page 54
Waters Corporation Page 75, OBC
All the data produced by this process is sent
back to Perthera, which also receives the
patient’s previous treatment history detailing
former therapeutic regimens and any toxicities
experienced. These data are aggregated into a
report which is sent to a cloud-based, virtual
tumor board, made up of medical experts from
anywhere in the world. This panel of experts
then provides a schema of ranked treatment
options, which can include anything from an
FDA-approved drug the patient hasn’t tried
yet to an off-label one, all the way down to
matched clinical trials filtered for geographical
proximity to the patient. “We don’t tell the
doctor what to do,” explained Petricoin. “But
we remove the stress and hassle of coordinating
multi-omics precision medicine from the
patient and their doctor…”
Because Perthera is not a commercial lab, or
indeed, a lab at all, it sits at the top of this
process and can pick and choose from the
companies and institutions that it feels are the
most synergistic – “Those that provide the most
multi-omics solutions,” Petricoin elaborated.
As long as the technologies are commercially
available and CLIA/CAP accredited, they can
be considered. “We don’t have any financial
connections with any of these companies,
we keep an arms-length relationship with them.
This enables us to stop using any of the tech-
nologies the second they become obsolete.” He
further added, “Perthera is driven to identify
companies that are offering the best molecular
profiling solutions; we would be out of business
if we didn’t constantly survey the field to ensure
our patients and their treating oncologists are
armed with the absolute best multi-omic data to
make the best treatment decisions.”
Shifting The Balance
With the democratization of precision medicine
and its centralization into ‘hub’ companies like
Perthera, the balance may shift further towards
multi-omics, becoming less weighted in favor
of genomics. But that is not to say it must shift
entirely. Campbell is in agreement, “Although
genes are not the full equation, they are
definitely part of the equation.” Petricoin
echoed this, “DNA is the information archive,
but it’s the proteins that do the work and
indeed are the drug targets for nearly every
targeted inhibitor and immunotherapy.
The first will give you an idea of what you’re
looking at, the latter will give you direct
information about the state of a disease and the
molecular target that is the most ‘actionable.’”
Narain also believes that precision medicine
is on the right track, but it will still throw out
a few surprises as it heads further towards
multi-omics: “It’s slowly moving in the right
direction; however, we need to go way deeper
than just genomics and get used to the idea of
a few unexpected finds. If we could make those
small but fundamental changes in the way that
we approach precision medicine, then we’ll be
making progress.”
(*A research field combining therapeutics and diagnostics.)
References
1. Welter D, MacArthur J, Morales J, Burdett T, Hall P, Junkins H, Klemm A, Flicek P, Manolio T, Hindorff L, and Parkinson H.The NHGRI GWAS Catalog, a curated resource of SNP-trait associations.Nucleic Acids Research, 2014, Vol. 42 (Database issue): D1001-D1006.
CLIA = the Clinical Laboratory Improvement Amendments of 1988 are United States federal regulatory standards that oversee and grant accreditation for laboratory developed tests (LDTs). They apply to all clinical laboratory testing performed on humans in the United States, except clinical trials and basic research.
CAP = College of American Pathologists
Theranostics = A research field combining diagnostics and therapeutics, in which molecular diagnostic tests are developed in tandem with targeted therapeutics.
Deborah Grainger, Ph.D, is an independent science
writer with a wide-ranging subject interest. Equally
comfortable covering topics from complex neuroscience
to drug combinations in immune oncology, she honed
her writing skills working in communications for five years
at a biotechnology SME. Deborah also holds a PhD in cell
signaling from the University of Manchester.
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