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Clinical Laboratories and Pathology Groups

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Metabolomics Promises to Provide New Diagnostic Biomarkers, Assays for Personalized Medicine and Medical Laboratories

Researchers are finding multiple approaches to metabolomic research and development involving disparate technology platforms and instrumentation

Human metabolome has been discovered to be a wealth of medical laboratory biomarkers for diagnosis, therapy, and patient monitoring. Because it can provide a dynamic phenotype of the human body, there are many potential clinical laboratory applications that could arise from metabolomics, the study of metabolites.

Researchers are discovering numerous ways the expanding field of metabolomics could transform the future of healthcare. However, to fully exploit the potential of human metabolome, developers must choose from various approaches to research.

“The metabolites we’re dealing with have vast differences in chemical properties, which means you need multi-platform approaches and various types of instrumentation,” James MacRae, PhD, Head of Metabolomics at the Francis Crick Institute in London, told Technology Networks. “We can either use an untargeted approach—trying to measure as much as possible, generating a metabolic profile—or else a more targeted approach where we are focusing on specific metabolites or pathways,” he added.

A multi-platform approach means different diagnostic technologies required to assess an individual’s various metabolomes, which, potentially, could result in multi-biomarker assays for medical laboratories.

Measuring All Metabolites in a Cell or Bio System

Metabolomics is the study of small molecules located within cells, biofluids, tissues, and organisms. These molecules are known as metabolites, and their functions within a biological system are cumulatively known as the metabolome.

Metabolomics, the study of metabolome, can render a real-time representation of the complete physiology of an organism by examining differences between biological samples based on their metabolite characteristics.

“Metabolomics is the attempt to measure all of the metabolites in a cell or bio system,” explained MacRae in the Technology Networks article. “You have tens of thousands of genes, of which tens of thousands will be expressed—and you also have the proteins expressed from them, which will then also be modified in different ways. And all of these things impact on a relatively small number of metabolites—in the thousands rather than the tens of thousands. Because of that, it’s a very sensitive output for the health or physiology of your sample.

“With that in mind, metabolomics has great potential for application in most, if not all, diseases—from diabetes, heart disease, cancer, HIV, autoimmune disease, parasitology, and host-pathogen interactions,” he added.

State-of-the-art metabolomic technologies

The graphic above is taken from a study published in the Journal of the American College of Cardiology (JACC). It notes, “State-of-the-art metabolomic technologies give us the ability to measure thousands of metabolites in biological fluids or biopsies, providing us with a metabolic fingerprint of individual patients. These metabolic profiles may serve as diagnostic and/or prognostic tools that have the potential to significantly alter the management of [chronic disease].” (Image and caption copyright:Journal of the American College of Cardiology.)

There are four major fields of study that are collectively referred to as the “omics.” In addition to metabolomics, the remaining three are:

•                  Genomics: the study of DNA and genetic information within a cell;

•                  Proteomics: the large-scale study of proteins; and,

•                  Transcriptomics: the study of RNA and differences in mRNA expressions.

Researchers caution that metabolomics should be used in conjunction with other methods to analyze data for the most accurate results.

“Taking everything together—metabolic profiling, targeted assays, label incorporation and computational models, and also trying to associate all of this with proteomics and

genomics and transcriptomic data—that’s really what encapsulates both the power and also the challenges of metabolomics,” MacRae explained.

Metabolome in Precision Medicine

Metabolomics may also have the ability to help researchers and physicians fine-tune therapies to meet the specific needs of individual patients.

“We know we’re all very different and we don’t respond to drugs in the same way, so we could potentially use metabolomics to help select the best treatment for each individual,” Warwick Dunn, PhD, Senior Lecturer in Metabolomics at the University of Birmingham, Director of Mass Spectrometry, Phenome Center Birmingham, and, Co-Director, Birmingham Metabolomics Training Center, UK, told Technology Networks.

“Our genome is generally static and says what might happen in the future. And the metabolome at the other end is the opposite—very dynamic, saying what just happened or could be about the happen,” Dunn explained. “So, we could apply it to identify prognostic biomarkers, for example, to predict if someone is at greater risk of developing diabetes five to ten years from now. And if you know that, you can change their lifestyle or environment to try and prevent it.”

Metabolomics continues to tap the many diagnostic possibilities posed by the human metabolome. And, the resulting human biomarkers derived from the research could result in a rich new vein of medical laboratory assays.

—JP Schlingman

Related Information:

Metabolomics and Health: On the Cusp of a Revolution

‘Metabolomics’ Distinguishes Pancreatic Cancer from Pancreatitis

Using Metabolomics to Prevent Colon Cancer

Applications of Metabolomics

The Emerging Role of Metabolomics in the Diagnosis and Prognosis of Cardiovascular Disease

Metabolomics Takes Another Step Forward as Methodology for Clinical Laboratory Testing with Development of an Assay for the Diagnosis of Concussion


Developments in MALDI Mass Spectrometry Could Lead to Advancements in Cancer Imaging Technologies for Anatomic Pathologists and Clinical Laboratories

This may especially benefit cancer research and treatment thanks to MALDI’s ability to provide pathologists with a view of the whole-tissue micro-environment

Though it may be years before Matrix-Assisted Laser Desorption Ionization (MALDI) mass spectrometry finds use in clinical applications, recent developments show medical laboratories and anatomic pathologists how one type of technology is being rapidly adapted for use in diagnosing cancers.

Richard Drake, PhD, Director of the Medical University of South Carolina (MUSC) Proteomics Center, notes the importance of MALDI to cancer research. “In the clinic, there has to be something that will facilitate looking at all this data—tools that will let the pathologists look at it as well as the mass spec person,” Drake told GenomeWeb.

“It has been known for decades that glycosylation changes on the cell surface promotes cancer progression and the way the immune system sees a tumor or doesn’t see a tumor,” he explained. “That’s the advantage of MALDI imaging. You’re looking at the whole tissue micro-environment, and particularly for cancer it turns out to be important.”

Imaging Mass Spectrometry Applications for Anatomic Pathology

MALDI uses mass spectrometry imaging technology to enable high-molecular identification and an overall view of tissue. It differs from liquid chromatography-mass spectrometry (LC-MS), which is a chemical analysis technique.

An article by News-Medical describes in detail how MALDI technology works:

“MALDI imaging works through the utilization of a matrix, an acidic aromatic molecule that absorbs energy of the same wavelength produced by the irradiating laser. The matrix transfers the substance being examined to the gas state, thereby producing ionization in a three-step process:

1.     “Thin sample sections on a metal slide are first covered with the matrix and the procedure for extracting molecules of interest from the tissue into the matrix begins. The matrix can be applied both manually and automatically.

2.     “The laser irradiates the sample only in the matrix layer, meaning the underlying tissue remains intact.

3.     “The released molecules are transferred to the gas state as the matrix absorbs the laser energy. Ions are formed due to the addition or removal of protons when in the gas state.

“The irons are required for further analysis via the mass spectrometer. The metal slide is placed into a MALDI mass spectrometer where the spatial distribution of the biological molecules is mapped. Within the mass spectrometer, the tissue specimen is raster scanned forming a mass spectrum for each spot measured. Image processing software is then required to import the data from the mass spectrometer to allow visualization of the image produced.”


The above schematic illustrates “the identification of bacteria and yeast by MALDI-TOF MS using the intact-cell method. Bacterial or fungal growth is isolated from plated culture media (or can be concentrated from broth culture by centrifugation in specific cases) and applied directly onto the MALDI test plate. Samples are then overlaid with matrix and dried. The plate is subsequently loaded into the MALDI-TOF MS instrument and analyzed by software associated with the respective system, allowing rapid identification of the organism.” (Caption and image copyright: Clinical Microbiology Reviews/American Society for Microbiology.)

MALDI in Clinical Laboratories

MALDI experts at MUSC worked with researchers at Bruker Corporation, a developer of scientific instruments and analytical diagnostic solutions for cell biology, preclinical imaging, clinical phenomics and proteomics research, clinical microbiology, and for molecular pathology research. Bruker is reportedly working with labs in Europe on MALDI-based assays for clinical use.

Developing MALDI applications for use in clinical laboratories and anatomic pathology groups could result in major improvements. Imaging mass spectrometry could:

  • make more molecular information available;
  • reduce pathology’s subjectivity and intra-observer nature;
  • enable more accuracy and ability to duplicate current pathology assays; and,
  • pave the way for new assays to be made.

“MALDI-IMS [imaging mass spectrometry] identifies the distributions of proteins, peptides, small molecules, lipids, and drugs and their metabolites in tissues, with high spatial resolution. This unique capacity to directly analyze tissue samples without the need for lengthy sample preparation reduces technical variability and renders MALDI-IMS ideal for the identification of potential diagnostic and prognostic biomarkers and disease gradation,” noted authors of a MALDI study published in the July 2017 edition of Biochimica et Biophysica Acta Proteins and Proteomics.

“You can take a slide of tissue and essentially do metabolomics on it so that you can look at the intricate nature of what metabolism is happening within a tissue,” James MacRae, PhD, Head of Metabolomics at the Francis Crick Institute in London, told Technology Networks, which described development of new mass spectrometry imaging technologies as “potentially game-changing.”

Mass Spectrometry in Clinical Laboratories

This is just the latest in a string of scientific developments involving mass spectrometry over the past decade that are potential boons to clinical laboratories. In “Is Mass Spectrometry Ready to Challenge ELISA for Medical Laboratory Testing Applications?Dark Daily reported on the development of a new technique from the Department of Energy’s Pacific Northwest National Laboratory that uses mass spectrometry to identify protein biomarkers associated with cancer and other diseases. Researchers dubbed the technique PRISM, which stands for Proteomics Research Information System and Management.

And in “Swiss Researchers Use New Mass Spectrometry Technique to Obtain Protein Data, Create Strategy That Could Lead to Clinical Laboratory Advances in Personalized Medicine,” Dark Daily reported on researchers at the Swiss Federal Institute of Technology in Lausanne and ETH Zurich who developed a new way to use mass spectrometry to explain why patients respond differently to specific therapies. The method potentially could become a useful tool for clinical laboratories that want to support the practice of precision medicine.

As mass spectrometry’s role in clinical laboratories continues to expand, MALDI technology development and research could eventually lead to tools and applications that enhance how anatomic pathologist view tissue specimens in the medical laboratory. Though the research is ongoing, the technology seems particularly suited to cancer research and treatment.

—Donna Marie Pocius

Related Information:

Technical Advances Position MALDI Imaging as Plausible Tool for Clinical Pathology

Bruker Introduces Novel Mass Spectrometry Solutions for MALDI Imaging, Metabolomics, Proteoform Profiling, and Toxicology at ASMS 2017

The Proteomics of Prostate Cancer Exosomes

MALDI Imaging

Matrix-Assisted Laser Desorption Ionization–Time of Flight Mass Spectrometry: A Fundamental Shift in the Routine Practice of Clinical Microbiology

Metabolomics and Health – On the Cusp of a Revolution

Is Mass Spectrometry Ready to Challenge ELISA for Medical Laboratory Testing Applications?

Swiss Researchers Use New Mass Spectrometry Technique to Obtain Protein Data, Create Strategy That Could Lead to Clinical Laboratory Advances in Personalized Medicine

Precision Medicine Summit Feb. 21, 2018

Human Antibodies in Medical Laboratory May Be Key to Immunity and Preventing Diseases Such as Influenza A

Scientists with Francis Crick Institute and Ragon Institute have successfully created human antibodies in vitro that can be made to recognize specific antigens in the human body; Could lead to new treatments for cancer and other infectious diseases

It’s been long-recognized that the ability to design human antibodies customized to recognize specific antigens could be a game-changer in the diagnosis and treatment of many diseases. It would enable the creation of useful new clinical laboratory tests, vaccines, and similar therapeutic modalities.

Now an international research team has published the findings of its novel technique that was developed to generate human antibodies in vitro. The research was conducted at the Ragon Institute of Massachusetts General Hospital (MGH), Massachusetts Institute of Technology (MIT), Harvard, and the Francis Crick Institute in London.

Antibodies and antigens are used in a large number of clinical laboratory and anatomic pathology tests and assays. In many cases, animal antibodies/antigens are used in test kits because they attract and bind to specific human antibodies/antigens that are biomarkers for diagnoses. Thus, as this technology is validated and further developed, it could be the source of useful biomarkers for lab tests as well as for vaccines.

Antibodies—also referred to as immunoglobulins—are made by the body’s B-lymphocytes (B cells) in response to antigens, such as bacteria, viruses, or other harmful substances. Each antibody has a special bearing on a particular antigen. For example, the human immunodeficiency virus (HIV) antibody and HIV antigen (p24) test screens and diagnoses people for HIV infection, explained LabTestsOnline.

Many medical laboratory tests use animal antibodies and antigens. But what if human antibodies could be generated and stimulated to recognize specific human antigens? That’s what the researchers believe they have done, according to a press release.

The Ragon Institute at MGH, MIT, and Harvard (above) was established in 2009 to find an HIV vaccine and to be a worldwide leader in the study of immunology. The Francis Crick Institute, formed in 2015, is a biomedical research institute using biology to understand health and disease. (Photo copyright: The Ragon Institute.)

The researchers know the novel technique they developed for generating human antibodies in vitro needs further development and validation. If this happens, the technique could one day be the source of useful biomarkers for medical lab tests, and may be a way to prevent infectious diseases.

“Specifically, it should allow the production of these antibodies within a shorter time frame in vitro and without the need for vaccination or blood/serum donation from recently infected or vaccinated individuals,” said Facundo D. Batista, PhD, in the press release. Batista is Principle Investigator with the Ragon Institute and led the research teams. “In addition, our method offers the potential to accelerate the development of new vaccines by allowing the efficient evaluation of candidate target antigens.”

Researchers Aim to Make Human Antibodies in Medical Laboratory

This international team of researchers sought to replicate in the lab—using patient blood samples—a natural human process for creation of antibodies from B cells. This is the process they wished to replicate:

·       Antibodies are made by the body’s B cells;

·       An antigen molecule is recognized by a B cell;

·       Plasma cells (able to secrete antibodies) develop;

·       An antibody binds to a particular antigen to fight an infection.

“B lymphocytes (B cells) play a critical role in adaptive immunity, providing protection from pathogens through the production of specific antibodies. B cells recognize and respond to pathogen-derived antigens through surface B cell receptors,” the researchers wrote in The Journal of Experimental Medicine (JEM).

Nanoparticles Key to the Approach

But finding an exact antigen is only one part of the B cell’s job. In the lab, B cells also need a trigger that enables them to grow and develop into plasma cells, which are key to fighting disease, the researchers noted.

“The in vitro activation of B cells in an antigen-dependent manner is difficult to achieve,” the authors stated in the JEM. “To overcome limitations, we developed a novel in vitro strategy to stimulate human B cells with streptavidin nanoparticles conjugated to both CpG and antigen. B cells producing antigen-specific antibodies were identified, quantified, and characterized to determine the antibody repertoire.”

According to the press release, “CpG oligonucleotides internalize into B cells that recognize the specific antigen.”

The statement, which garnered worldwide attention, noted the following steps taken by the researchers:

·       B cells from patient blood samples were isolated;

·       Then, they were treated with tiny nanoparticles coated with both CpG oligonucleotides and the right antigen;

·       These DNA molecules are unique, because they can activate toll-like receptor 9 (TLR9);

·       TLR9 develops into antibody-secreting plasma cells.

Results: Antibodies for Tetanus, Influenza, HIV

This method, according to the scientists, could be used in further research to develop antibodies to treat infectious diseases and cancer.

According to The Times of India,

·       “The team successfully demonstrated their approach using various bacterial and viral antigens, including the tetanus toxoid and proteins from several strains of influenza A;

·       “In each case, the researchers were able to produce specific, high-affinity antibodies in just a few days. Some of the anti-influenza antibodies generated by the technique recognized multiple strains of the virus and were able to neutralize its ability to infect cells;

·       “The procedure does not depend on the donors having been previously exposed to any of these antigens through vaccination or infection; and,

·       “Researchers were able to generate anti-HIV antibodies from B cells isolated from HIV-free patients.”

Research Suggests More Possibilities

While this highly scientific study may not be on the radar of most anatomic pathologists and medical laboratory leaders at the moment, it holds enormous promise to produce cures for infectious disease and more effective cancer treatments. This research project also demonstrates how new techniques using antibodies have the potential to create an entirely new generation of clinical laboratory assays that improve diagnostic accuracy and better inform physicians when they consider the most appropriate therapies for their patients.

—Donna Marie Pocius

Related Information:

Researchers Develop New Method to Generate Human Antibodies

Novel In Vitro Booster Vaccination to Rapidly Generate Antigen-Specific Human Monoclonal Antibodies

Human Antibodies Produced in Lab for First Time