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Clinical Laboratories and Pathology Groups

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Advancements That Could Bring Proteomics and Mass Spectrometry to Clinical Laboratories

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

Potential New Clinical Laboratory Urine Test for TB Could Speed Up Diagnosis and Treatment of Disease That Kills 1.7 Million People Each Year

Public health agencies and physicians would gain access to accurate, rapid dip-stick test that could give results similar to a pregnancy test

Tuberculosis is a major killer that ranks alongside HIV/AIDS as a leading cause of death worldwide. This deadly disease takes the lives of more than a million people each year. And, unfortunately, traditional medical laboratory testing using X-rays, blood/skin/sputum specimens, or the new molecular diagnostic systems can be time consuming and expensive.

Now, scientists at George Mason University (GMU) in Virginia have developed a urine test for tuberculosis (TB) that could lead to a dip-stick technology that would accurately and rapidly diagnose the deadly lung disease. Similar to a pregnancy test, if successfully developed for use in clinical settings, the dip-stick could not only enable public health agencies to test for TB more effectively, but also allow primary care physicians and other doctors to easily test their patients for TB at the point of care. However, it also could mean clinical laboratories might find their participation.

Nearly All TB Deaths Occur in Resource Strapped Areas

Such a breakthrough would certainly be a boon to public health and global healthcare, especially in resource strapped areas of the world. According to the World Health Organization (WHO), more than 95% of the 1.7 million TB deaths each year occur in low- and middle-income countries. This is one reason why an inexpensive and easy-to-use detection method for diagnosing the lung disease has long been sought. TB is curable, particularly if diagnosed early.

With that goal in mind, an international team led by Alessandra Luchini, PhD, Associate Professor at GMU, and Lance Liotta, PhD, MD, co-director and co-founder of the GMU Center for Applied Proteomics and Molecular Medicine, developed the potentially revolutionary urine test that uses nanotechnology to measure a sugar molecule in urine that identifies TB with a high degree of accuracy. The scientists published their results in Science Translational Magazine.

George Mason University scientists Alessandra Luchini, PhD

George Mason University scientists Alessandra Luchini, PhD (above left), and Lance Liotta, MD, PhD (above right), head an international team that has developed a nanotechnology that may lead to a simple dipstick urine test to detect tuberculosis. Such a test could greatly impact medical laboratories by reducing the need for traditional lab tests. (Photo copyrights: George Mason University.)

While past attempts at developing an accurate urine test for TB failed to reliably detect low concentrations of the sugar entity lipoarabinomannan (LAM) in HIV-negative, TB-infected patients, the GMU team developed a technology capable of doing so.

According to New Scientist, the GMU team’s test “uses tiny molecular cages embedded with a special dye that can catch and trap these sugar molecules. This makes the test capable of detecting the sugar at low concentrations, making the technique as much as 1,000 times more accurate [than] previous methods for detecting TB in urine.”

“We can measure now what could never be measured before,” Liotta noted in a news release.

World Health Organization Recommends Not Using Serodiagnostic Blood Tests

Common methods to detect TB currently include microscopy of sputum samples—a fast and accurate but expensive detection method (that also can diagnosis drug resistant disease)—or a skin test. A third test for TB, an Interferon-Gamma Release Assay, provides results in less than 24 hours but cannot distinguish between active and latent infection. In 2011, the WHO issued a Policy Recommendation urging countries to stop using serodiagnostic blood tests to diagnose TB, calling these tests unreliable and inaccurate. X-rays, meanwhile, detect only advanced lung damage.

In the GMU study, 48 Peruvian patients were chosen, all with active pulmonary TB, none of whom was infected with HIV or previously had received treatment for TB. According to the research, TB infections were detected with greater than 95% sensitivity, with TB-positive, HIV-negative patients having detectably higher concentrations of LAM in their urine compared to the controls. Patients who had more advanced disease also had elevated LAM concentrations. Eight of nine patients who were smear-negative and culture-positive for TB tested positive for urinary LAM.

“The technology can be configured in a variety of formats to detect a panel of previously undetectable very-low-abundance TB urinary analytes … This technology has broad implications for pulmonary TB screening, transmission control, and treatment management for HIV-negative patients,” the study’s authors told Science.

While The Scientist reports the GMU urine test gives results in about 12 hours, Luchini’s goal is for that timeframe to be dramatically shortened as the test is refined.

“We showed that our technology could be used to measure several different kinds of markers for TB in the urine and could be configured as a rapid test similar to a pregnancy test,” Luchini said in a GMU news release.

According to the university, GMU researchers will continue their work in Peru, where students will begin testing hundreds of patients as part of a research study. Grants from the National Institutes of Health and the Bill and Melinda Gates Foundation are funding their work. Luchini told New Scientist her goal is to make their TB urine test easier to use and to test it on thousands more people.

If successful, she predicts the test could be commercially available for physicians and clinical laboratories to use within three years. GMU’s biotechnology partner Ceres Nanosciences will be commercializing the technology, with the aim of making the test available worldwide, the university said in a statement.

—Andrea Downing Peck

Related Information:

TB, or Not TB? At Last, a Urine Test Can Diagnose It Quickly

Urine Lipoarabinomannan Glycan in HIV-Negative Patients with Pulmonary Tuberculosis Correlates with Disease Severity

Mason Scientists Develop Nanotechnology-based Urine Test that Could Lead to Early TB Detection

Urine Test for TB Yields Results in 12 Hours

Tuberculosis Serodiagnostic Tests Policy Statement 2011

Tuberculosis Mortality Nearly Halved Since 1990

Tuberculosis Fact Sheet

In Its Second Year, Medical Home Program of CareFirst BCBS Produced $98 Million in Savings, along with Significant Quality Improvements

In Its Second Year, Medical Home Program of CareFirst BCBS Produced $98 Million in Savings, along with Significant Quality Improvements

One of the nation’s largest patient-centered medical home  (PCMH) programs has reduced costs dramatically and improved care quality for the second consecutive year. It recently reported the achievements produced during its first two years of operation.

This accomplishment is more evidence for pathologists and clinical laboratory executives that a properly implemented medical home program can deliver measurable gains in patient outcomes and corresponding reductions in the overall cost of care. In January 2011, CareFirst BlueCross BlueShield started a PCMH program for primary-care physicians (PCPs). It serves about 1 million members in Maryland, Washington, D.C., and northern Virginia.