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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.”

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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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