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Advancements That Could Bring Proteomics and Mass Spectrometry to Clinical Laboratories

Jan 13, 2020 | Laboratory Instruments & Laboratory Equipment, Laboratory Management and Operations, Laboratory News, Laboratory Operations, Laboratory Pathology, Laboratory Testing, Management & Operations

Experts list the top challenges facing widespread adoption of proteomics in the medical laboratory industry

Year-by-year, clinical laboratories find new ways to use mass spectrometry to analyze clinical specimens, producing results that may be more precise than test results produced by other methodologies. This is particularly true in the field of proteomics.

However, though mass spectrometry is highly accurate and fast, taking only minutes to convert a specimen into a result, it is not fully automated and requires skilled technologists to operate the instruments.

Thus, although the science of proteomics is advancing quickly, the average pathology laboratory isn’t likely to be using mass spectrometry tools any time soon. Nevertheless, medical laboratory scientists are keenly interested in adapting mass spectrometry to medical lab test technology for a growing number of assays.

Molly Campbell, Science Writer and Editor in Genomics, Proteomics, Metabolomics, and Biopharma at Technology Networks, asked proteomics experts “what, in their opinion, are the greatest challenges currently existing in proteomics, and how can we look to overcome them?” Here’s a synopsis of their answers:

Lack of High Throughput Impacts Commercialization

Proteomics isn’t as efficient as it needs to be to be adopted at the commercial level. It’s not as efficient as its cousin genomics. For it to become sufficiently efficient, manufacturers must be involved.

John Yates III, PhD, Professor, Department of Molecular Medicine at Scripps Research California campus, told Technology Networks, “One of the complaints from funding agencies is that you can sequence literally thousands of genomes very quickly, but you can’t do the same in proteomics. There’s a push to try to increase the throughput of proteomics so that we are more compatible with genomics.”

For that to happen, Yates says manufacturers need to continue advancing the technology. Much of the research is happening at universities and in the academic realm. But with commercialization comes standardization and quality control.

“It’s always exciting when you go to ASMS [the conference for the American Society for Mass Spectrometry] to see what instruments or technologies are going to be introduced by manufacturers,” Yates said.

There are signs that commercialization isn’t far off. SomaLogic, a privately-owned American protein biomarker discovery and clinical diagnostics company located in Boulder, Colo., has reached the commercialization stage for a proteomics assay platform called SomaScan. “We’ll be able to supplant, in some cases, expensive diagnostic modalities simply from a blood test,” Roy Smythe, MD, CEO of SomaLogic, told Techonomy.


The graphic above illustrates the progression mass spectrometry took during its development, starting with small proteins (left) to supramolecular complexes of intact virus particles (center) and bacteriophages (right). Because of these developments, today’s medical laboratories have more assays that utilize mass spectrometry. (Photo copyright: Technology Networks/Heck laboratory, Utrecht University, the Netherlands.)

Achieving the Necessary Technical Skillset

One of the main reasons mass spectrometry is not more widely used is that it requires technical skill that not many professionals possess. “For a long time, MS-based proteomic analyses were technically demanding at various levels, including sample processing, separation science, MS and the analysis of the spectra with respect to sequence, abundance and modification-states of peptides and proteins and false discovery rate (FDR) considerations,” Ruedi Aebersold, PhD, Professor of Systems Biology at the Institute of Molecular Systems Biology (IMSB) at ETH Zurich, told Technology Networks.

Aebersold goes on to say that he thinks this specific challenge is nearing resolution. He says that, by removing the problem created by the need for technical skill, those who study proteomics will be able to “more strongly focus on creating interesting new biological or clinical research questions and experimental design.”

Yates agrees. In a paper titled, “Recent Technical Advances in Proteomics,” published in F1000 Research, a peer-reviewed open research publishing platform for scientists, scholars, and clinicians, he wrote, “Mass spectrometry is one of the key technologies of proteomics, and over the last decade important technical advances in mass spectrometry have driven an increased capability of proteomic discovery. In addition, new methods to capture important biological information have been developed to take advantage of improving proteomic tools.”

No High-Profile Projects to Stimulate Interest

Genomics had the Human Genome Project (HGP), which sparked public interest and attracted significant funding. One of the big challenges facing proteomics is that there are no similarly big, imagination-stimulating projects. The work is important and will result in advances that will be well-received, however, the field itself is complex and difficult to explain.

Emanuel Petricoin, PhD, is a professor and co-director of the Center for Applied Proteomics and Molecular Medicine at George Mason University. He told Technology Networks, “the field itself hasn’t yet identified or grabbed onto a specific ‘moon-shot’ project. For example, there will be no equivalent to the human genome project, the proteomics field just doesn’t have that.”

He added, “The equipment needs to be in the background and what you are doing with it needs to be in the foreground, as is what happened in the genomics space. If it’s just about the machinery, then proteomics will always be a ‘poor step-child’ to genomics.”

Democratizing Proteomics

Alexander Makarov, PhD, is Director of Research in Life Sciences Mass Spectrometry (MS) at Thermo Fisher Scientific. He told Technology Networks that as mass spectrometry grew into the industry we have today, “each new development required larger and larger research and development teams to match the increasing complexity of instruments and the skyrocketing importance of software at all levels, from firmware to application. All this extends the cycle time of each innovation and also forces [researchers] to concentrate on solutions that address the most pressing needs of the scientific community.”

Makarov describes this change as “the increasing democratization of MS,” and says that it “brings with it new requirements for instruments, such as far greater robustness and ease-of-use, which need to be balanced against some aspects of performance.”

One example of the increasing democratization of MS may be several public proteomic datasets available to scientists. In European Pharmaceutical Review, Juan Antonio Viscaíno, PhD, Proteomics Team Leader at the European Bioinformatics Institute (EMBL-EBI) wrote, “These datasets are increasingly reused for multiple applications, which contribute to improving our understanding of cell biology through proteomics data.”

Sparse Data and Difficulty Measuring It

Evangelia Petsalaki, PhD, Group Leader EMBL-EBI, told Technology Networks there are two related challenges in handling proteomic data. First, the data is “very sparse” and second “[researchers] have trouble measuring low abundance proteins.”

Petsalaki notes, “every time we take a measurement, we sample different parts of the proteome or phosphoproteome and we are usually missing low abundance players that are often the most important ones, such as transcription factors.” She added that in her group they take steps to mitigate those problems.

“However, with the advances in MS technologies developed by many companies and groups around the world … and other emerging technologies that promise to allow ‘sequencing’ proteomes, analogous to genomes … I expect that these will not be issues for very long.”

So, what does all this mean for clinical laboratories? At the current pace of development, its likely assays based on proteomics could become more common in the near future. And, if throughput and commercialization ever match that of genomics, mass spectrometry and other proteomics tools could become a standard technology for pathology laboratories.

—Dava Stewart

Related Information:

5 Key Challenges in Proteomics, As Told by the Experts

The Evolution of Proteomics—Professor John Yates

The Evolution of Proteomics—Professor Ruedi Aebersold

The Evolution of Proteomics—Professor Emanuel Petricoin

The Evolution of Proteomics—Professor Alexander Makarov

The Evolution of Proteomics—Dr. Evangelia Petsalaki

For a Clear Read on Our Health, Look to Proteomics

Recent Technical Advances in Proteomics

Emerging Applications in Clinical Mass Spectrometry

HPP Human Proteome Project

Open Data Policies in Proteomics Are Starting to Revolutionize the Field

Native Mass Spectrometry: A Glimpse Into the Machinations of Biology

‘Barcoding’ Cells in Nematodes Could Bring Advances and New Medical Laboratory Tools for Treatment of Cancer and Other Chronic Diseases

Nov 17, 2017 | Laboratory Instruments & Laboratory Equipment, Laboratory Management and Operations, Laboratory News, Laboratory Operations, Laboratory Pathology, Laboratory Testing, Management & Operations

Ongoing research at the University of Washington promises new methods for identifying and cataloging large numbers of cells quickly, which could lead to more individualized treatments in support of precision medicine initiatives

Researchers have found a new method for identifying specific cell types by groups, a breakthrough that some experts say could lead to new and more accurate methods for diagnosing and treating disease in individual patients, and new tools for fighting cancer and other chronic diseases. If this happens, both clinical laboratories and anatomic pathology labs would benefit from this technology.

A study published in the journal Science titled, “Comprehensive Single-Cell Transcriptional Profiling of a Multicellular Organism,” describes advances in cataloging cells that are much faster than the traditional method of using a microscope. The research is still in the experimental stage, but it is being hailed as both exciting and promising by experts in the field.

Barcoding Large Numbers of Cells for Viewing Simultaneously

To test their method, researchers from the University of Washington (UW) sequenced each cell of an individual Caenorhabditis elegans (nematode). Nematodes are transparent roundworms that have been extensively studied making them ideal for the UW study, since much information exists about their cellular structure.

The researchers developed a strategy they dubbed “single-cell combinatorial indexing RNA sequencing,” or “sci-RNA-seq” for short, to profile the transcriptomes of nuclei. A New York Times article on the study describes sci-RNA-seq as a kind of barcoding that shows which genes are active in each cell.

“We came up with this scheme that allows us to look at very large numbers of cells at the same time, without ever isolating a single cell,” noted Jay Shendure, PhD, MD, Professor of Genome Sciences at the University of Washington.

The UW researchers used sci-RNA-seq to measure the activity in 42,035 cells at the same time. Once all of the cells were tagged, or barcoded, the researchers broke them open so the sequences of tags could be read simultaneously.

“We defined consensus expression profiles for 27 cell types and recovered rare neuronal cell types corresponding to as few as one or two cells,” wrote the researchers in their published study.

Because such a rich body of research on nematodes exists, the researchers could easily compare the results that got to those procured in previous studies.

Jay Shendure, MD, PhD (above), Professor of Genomic Sciences at the University of Washington, and an Investigator at the Howard Hughes Medical Institute, was just a graduate student when his work with genetics led to the development of today’s next-generation gene sequencing technologies. His new cell-type identification technology could eventually be used by clinical laboratories and anatomic pathology groups to diagnose disease. (Photo copyright: Howard Hughes Medical Institute.)

One Giant Leap for Medical Diagnostics

Identifying cell types has been a challenge to the medical community for at least 150 years. It is important for scientists to understand the most basic unity of life, but it has only been in the last few years that researchers have been able to measure transcriptomes in single cells. Even though the research so far is preliminary, the scientific community is excited about the results because—should the methods be refined—it could mean a great leap forward in the field of cell-typing.

However, the study did not identify all of the cell types known to exist in a nematode. “We don’t consider this a finished project,” stated Shendure in a New York Times article.

Nevertheless, researchers not associated with the study feel confident about the promise of the work. Cori Bargmann, PhD, a neurobiologist and Torsten N. Wiesel Professor at The Rockefeller University, and an Investigator for the Howard Hughes Medical Institute from 1995 to 2016, states that the results “will be valuable for me and for the whole field,” adding, “Of course, there’s more to do, but I am pretty optimistic that this can be solved.”

“The ability to measure the transcriptomes of single cells has only been feasible for a few years, and is becoming an extremely popular assay,” wrote Valentine Svensson, predoctoral fellow et al, of EMBL-EBI in the UK, in a paper titled, “Exponential Scaling of Single-Cell RNA-Seq in the Last Decade.” He added, “Technological developments and protocol improvements have fueled a consistent exponential increase in the numbers of cells studied in single cell RNA-seq analyses.” The UW research represents another such improvement.

Human Cell Atlas—Understanding the Basis of Life Itself

There are approximately 37-trillion cells in the human body and scientists have long believed there are 200 different cell types. Thus, there is an enormous difference between a nematode and a human body. For medical science to benefit from these studies, massive numbers of human cells must be identified and understood. Efforts are now underway to catalog and map them all.

The Human Cell Atlas (HCA) is an effort to catalog all of those disparate cell types. The mission of HCA is “To create comprehensive reference maps of all human cells—the fundamental units of life—as a basis for both understanding human health and diagnosing, monitoring, and treating disease.”

According to HCA’s website, having the atlas completed will impact our understanding of every aspect of human biology, from immunologic diseases to cancer. Aviv Regev, PhD, of the Broad Institute at MIT, who also is an Investigator with the HHMI and is co-chair of the organizing committee at the Human Cell Atlas notes, “The human cell atlas initiative will work through organs, tissues, and systems.”

One of the many complications of creating the atlas is that the locations of cells vary in humans. “The trick,” Regev noted in the New York Times article, “is to relate cells to the place they came from.” This would seem to be at the heart of the UW researchers’ new method for “barcoding” groups of cells.

Just as sequencing the entire human genome has brought about previously unimagined advances in science, so too will the research being conducted at the University of Washington, as well as the completion of the Human Cell Atlas Project. It is possible that pursuing the goal of quickly identifying and cataloging cells will lead to advances in anatomic pathology, and allow medical laboratory scientists to better interpret genetic variants, ultimately bringing healthcare closer to the delivery of true precision medicine.

—Dava Stewart

Related Information:

Comprehensive Single-Cell Transcriptional Profiling of a Multicellular Organism

A Speedier Way to Catalog Human Cells (All 37 Trillion of Them)

Exponential Scaling of Single-Cell RNA-Seq In the Last Decade

Human Cell Atlas

Genetic Fingerprint Helps Researchers Identify Aggressive Prostate Cancer from Non-Aggressive Types and Determine if Treatment Will Be Effective

Big Data Projects at Geisinger Health Are Beginning to Help Physicians Speed Up Diagnosis and Improve Patient Care

Biomarker Trends Are Auspicious for Pathologists and Clinical Laboratories

Pathologists and Clinical Laboratories May Soon Have a Test for Identifying Cardiac Patients at Risk from Specific Heart Drugs by Studying the Patients’ Own Heart Cells

With Launch of RNAcentral Database, Pathologists Now Have Unprecedented Access to RNA Data

Mar 13, 2015 | Laboratory Management and Operations, Laboratory News, Laboratory Operations, Laboratory Pathology, Management & Operations

New public database gives clinical laboratory researchers a single, searchable source for non-coding RNA data, thus aiding development of new diagnostic assays

Clinical laboratories involved in next-generation gene sequencing have a new single searchable database for RNA. Experts say that this database should help research and development of medical laboratory tests for clinical purposes.

The launch of RNAcentral now provides RNA biologists and other researchers with an open resource that offers integrated access to a comprehensive, up-to-date set of non-coding RNA sequences. This is a first step to building a repository of information for non-coding RNAs that is similar to the Universal Protein Resource (UniProt) database for proteins.

RNAcentral is the brainchildof the RNAcentral Consortium, a large international collaboration of more than 30 expert databases that specialize in different types of non-coding RNAs. So far, 12 of these databases have been integrated into RNAcentral. The project is hosted by the European Bioinformatics Institute and funded by a United Kingdom Biotechnology and Biological Sciences Research Council (BBSRC) grant. (more…)

Boston Pathologists at the Forefront of Whole Human Genome Sequencing

Nov 26, 2010 | Laboratory News, Laboratory Pathology

1000 Genome Project publishes database of 800 whole human genome sequences


More than 800 whole human genomes were sequenced and the data was recently made available in a public database by the 1000 Genomes Project. This development is a reminder to medical laboratories and pathologists that clinical use of whole human genome sequences is fast approaching.

It is possible for clinical laboratory managers to access an article in the journal Nature that describes the work of the 1000 Genomes Project during this four-year pilot phase. The article is available on the Nature website as a PDF download.

(more…)

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