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For Proteomics, 2014 Marked by Interest, Critiques from the Broader Community

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NEW YORK (GenomeWeb) – From scientific collaborations to corporate acquisitions, 2014 was a year in which proteomics drew significant interest from the broader scientific community, with the attention serving to highlight the field's capabilities and potential as well as its current limitations. 

Perhaps most notably, 2014 saw the rise of proteogenomics, with a number of researchers combining proteomic and genomic experiments with the aim of shedding light on both levels of data.

While still in its early stages, proteogenomics has become an area of considerable research activity, and this year saw a number of papers and collaborations in the field. 

On the commercial side of things, AB Sciex and Illumina announced in October their OneOmics partnership, under which AB Sciex will place its Swath Proteomics Cloud Tool Kit — a suite of informatics tools for use with the company's Swath mass spec technology — in Illumina's BaseSpace cloud computing environment.

The effort, which aims to provide researchers more streamlined tools for integrating genomic and proteomic data, brings together two of the largest firms in the respective spaces and is arguably the most significant and concrete indication to date of vendor interest and investment in proteogenomics.

On the research front, a pair of Nature papers that used proteogenomic techniques to generate what were billed as nearly complete maps of the human proteome were among the most discussed studies in the field this year. 

The studies, one led by Johns Hopkins Universityresearcher Akhilesh Pandey and the other led by Technical University of Munich researcher Bernhard Kuster, used mass spec to identify, respectively, roughly 84 percent and 88 percent of the proteins in the human proteome. Additionally, both teams identified a number of novel proteins, including from various pseudogenes and non-coding RNAs.

Both studies, however, were criticized by researchers skeptical that the data supporting these novel identifications were of sufficiently high quality. The initial critique came from the genomics field in a letter published in Journal of Proteome Research by researchers with the Spanish National Cancer Research Centre (CNIO).

Additional criticisms followed, including at the Human Proteome Organization's 13th annual meeting in Madrid, where University of Michigan researcher Gil Omenn, chair of HUPO's Human Proteome Project (HPP), spent a portion of his presentation updating the progress of the HPP to critique the Kuster and Pandey papers, noting the various questions leveled at the groups by outside researchers.

Even with their flaws, however, the Nature papers represented valuable efforts at characterizing the human proteome, and provided an opportunity for discussion and refining of the methods used to get there, suggested some researchers. 

For instance, Albert Heck, chair of the Biomolecular Mass Spectrometry and Proteomics group at Utrecht University, told GenomeWeb that the CNIO team's criticisms were most likely correct, but that it wasn't necessarily something to "make a fuss of."

"The early genomes were full of mis-annotations and have seen thousands of corrections since [their initial release]," he said. "This is to be expected."

Swiss Federal Institute of Technology Zurich researcher Ruedi Aebersold likewise noted that "the good thing about the situation is that the data are generally high quality and they are accessible … [which] allows specialists like the [CNIO] group to reevaluate the interpretation of the data using different analysis strategies."

Another high-profile proteogenomics Nature study proved less controversial. In a paper published in the journal in July, researchers from the National Cancer Institute's Clinical Proteomic Tumor Analysis Consortium presented the findings of a proteogenomic analysis of 95 colon and rectal cancer tumors that combined mass spec-based proteomic data with genomic data previously generated by the NCI's Cancer Genome Atlas initiative.

The paper marked the first publication to emerge from the CPTAC program, a roughly $100 million endeavor that aims to combine protein biomarker discovery and verification studies in tumor tissue samples with genomic characterizations of those same samples done by TCGA. According to Vanderbilt University researcher Daniel Liebler, senior author on the study, the analysis identified several proteomic subtypes of the disease, including subtypes not apparent in the genomic data, and found that, broadly speaking, gene copy number variations are not predictive of protein expression.

Clinical condition

While the CPTAC findings are likely still years from making their way into the clinic, clinical proteomics did notch some wins in 2014.

Most significant – and in keeping with the notion of growing outside interest in proteomics – was Myriad Genetics' $270 million acquisition of protein biomarker firm Crescendo Bioscience. The substantial  acquisition price (for a proteomics Dx firm, at any rate) marked Crescendo — whose lead product, Vectra DA, is a test for assessing rheumatoid arthritis — as a success story in a market where, thus far, success has been hard to come by. In Q4 2014 Myriad reported $10.8 million in revenues from Vectra DA.

Integrated Diagnostics' Xpresys Lung cancer test also demonstrated some market momentum as the company announced in November that, roughly a year after launching, it has more than 200 million covered lives for the test, including agreements with UnitedHealthcare, MultiPlan, and preferred provider organizations FedMed, Fortified Provider Network, InterWest Health, Stratose, and Three Rivers Provider Network.

Using multiple-reaction monitoring mass spec to quantify the levels of 11 proteins in patient blood samples with the aim of identifying whether lung nodules detected via CT scans are likely benign, Xpresys is the first multiplexed proteomic test to go to market using MRM-MS on a triple quadrupole instrument. In May, Indi said it had secured $47.3 million in funding to drive commercialization of the product.

Astute Medical provided another clinical proteomics success story with the US launch in December of its NephroCheck test for acute kidney injury. The test measures the presence of two proteins – insulin-like growth-factor binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases (TIMP-2) – in urine, allowing clinicians to assess in about 20 minutes the risk of a patient developing AKI in the next 12 hours. The company received US Food and Drug Administration 510(k) clearance for the test in October.

Less promising were the performances of several other clinical proteomics firms. For instance, by year's end, BG Medicine had laid off more than half its staff, suspended payments to non-employee board directors, and received two delisting warnings from Nasdaq. On the company's Q3 2014 earnings call in November, CEO Paul Sohmer said it was considering "strategic alternatives" that could include joint ventures, a merger, or sale of the company, and that it had engaged Stifel, Nicolaus & Co. as a financial advisor to help it explore possible options.

Diagnostics firm Vermillion's situation is less dire, as the company in December announced an equity financing of up to $18.9 million. However, sales of its OVA1 ovarian cancer test remain flat at well below the volume needed to turn a profit, and the company is currently in the midst of yet another revamping, this time positioning itself as what then-CEO James LaFrance in November described as a "bio-analytic solutions company focused on gynecologic disease."

Vermillion plans to "expand beyond biomarkers and pure diagnostic measurement to include other modalities such as imaging, clinical risk factors, and patient data" in its testing, said LaFrance, who this week was replaced as president and CEO by Valerie Palmieri. He continues to serve as chairman of Vermillion's board.

Of course, at least Vermillion and BG Medicine are still around. The same can't be said for diabetes diagnostic firm Tethys Bioscience which, in late 2013, sold Health Diagnostic Laboratory its assets including biomarker, methodology, and technological patents; patent applications; and trademarks as well as clinical data and patient samples collected as part of both cross-sectional and longitudinal trials.

Founded in 2002, Tethys shut down after failing to win reimbursement from Medicare contractor CGS Administrators for its PreDx diabetes test. Over its lifetime, the company has raised more than $100 million in funding from parties including Intel Capital, Mohr Davidow Ventures, and Kleiner Perkins Caufield & Byers.

Cardiac test developer Aviir likewise dissolved, entering bankruptcy at the beginning of 2014. In April, former employees of the company led by former CEO Douglas Harrington launched a new firm, Global Discovery Biosciences, through which they plan to offer proteomic testing for the assessment of cardiovascular risk.

Single cells and Swath 

Beyond diagnostics, there was significant commercial activity on the tools front – with single-cell proteomics in particular cropping up as a hot area for vendor interest.

Fluidigm made the biggest splash in this space with its $207.5 million acquisition in January of mass cytometry firm DVS Sciences and its multi-parameter single-cell protein analysis platform, the CyTOF 2.

The purchase marked Fluidigm's continued expansion into protein analysis. Traditionally focused on single-cell genomics, the company signed in July 2013 a co-marketing deal with Olink Biosciences that combined the two firms' tools to create a high-throughput proteomics platform. In addition to the DVS purchase, Fluidigm announced in August plans to launch in 2015 a single-cell proteomics imaging platform based on the CyTOF instrument.

Also in 2014, NanoString obtained an exclusive option to license intellectual property to a proteomic assay developed by researchers atMassachusetts GeneralHospitalthat uses DNA-barcoded antibodies to simultaneously measure in the range of 100 proteins at single-cell sensitivity.

And in September, single-cell proteomics firm and University of California, Berkeley spinout Zephyrus Biosciences launched behind $1.9 million in funding.

Single-cell proteomics has lagged behind single-cell genomics due to the technical challenges involved. However, Fluidigm President and CEO Gajus Worthington told GenomeWeb in an interview regarding the CyTOF acquisition that the field has great potential from both a commercial and scientific standpoint.

Discussions with Fluidigm customers prior to the DVS buy made it "abundantly clear that to really do single-cell biology it is a requirement to have genomic and protein analysis," he said.

"The need was common really regardless of the application," he noted. "You had to have protein expression with genomics regardless of the biological question."

"We've been on a quest to find a robust, scalable, really enabling single-cell protein expression solution for years now,"Worthington said, adding that the DVS purchase was "just the beginning of what our ambitions are with respect to this field."

Another key area of vendor activity was data independent acquisition mass spec, where Thermo Fisher Scientific this year took direct aim at AB Sciex's Swath mass spec workflows with the release of several competing products. 

At the American Society for Mass Spectrometry annual conference inBaltimore, Thermo Fisher formally launched four different DIA workflows for use on platforms including the Q Exactive, the Orbitrap Fusion, and the Q Exactive HF.

AB Sciex, meanwhile, introduced a new DIA workflow of its own, Swath 2.0, an updated version of the original methodology, which played a significant role in driving the current interest in DIA mass spec.

And Waters executives told GenomeWeb that the company planned to beginincorporating into its instruments a new version of its MSE DIA method termed USMSE that was developed by researchers at Johannes Gutenberg University Mainz. The method uses ion mobility drift times to improve precursor fragmentation efficiency and, consequently, increase sensitivity and protein IDs.

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