Source: Kateryna Kon / Science Photo Library / Getty Images

While the clinical world has just begun to realize the promise of genomics to inform more precise care for individual patients, scientists also are pushing ahead with the development of clinical tools using other ’omics. The studies of proteins and metabolites—proteomics and metabolomics, respectively—offer considerable promise. In most cases, though, lots of lab work remains to be done before clinicians can benefit from proteomics or metabolomics.

First, the work in both fields is on the rise (See “On the Upswing”). Searches on PubMed revealed that published research on proteomics and metabolomics is increasing in general and in studies with medical and clinical implications.

When it comes to ’omics and medicine, cancer might come to mind first as the most likely application. That’s no surprise, especially since scientists and clinicians started thinking about ’omics-based tools for cancer some time ago. In 2007, for example, researchers from the University of Magdeburg in Germany wrote: “Proteomic studies have generated numerous datasets of potential diagnostic, prognostic, and therapeutic significance in human cancer.”

Despite the great opportunities for proteomic and metabolomic work on cancer care, work from these ’omic areas can also impact other aspects of medicine. From the London-based National Heart and Lung Institute, scientists explored the application of ’omics to heart disease, specifically a kind of high blood pressure called pulmonary arterial hypertension. “High-throughput platforms for plasma proteomics and metabolomics have identified novel biomarkers associated with clinical outcomes and provided molecular instruments for risk assessment,” they wrote. “There are methodological challenges to integrating these datasets, coupled to statistical power limitations inherent to the study of a rare disease, but the expectation is that this strategy will reveal novel druggable targets and biomarkers that will open the way to personalized medicine.”

Suraj Dhungana
Suraj Dhungana
manager of biomedical research global markets, Waters

When asked about the most exciting areas of translational metabolomics or proteomics research, Suraj Dhungana, manager of biomedical research global markets at Waters Corp., said, it “is the ability to take a biomarker or a panel of biomarkers and make it clinically relevant, or applicable, to studying cellular processes in a hypothesis-driven manner. The real strength of this approach depends on the ability to measure biomarkers reproducibly, complete large cohort studies in a timely manner, and identify true stable phenotypic markers, since stable biomarkers are reliable gauges of the phenotype.”

Even with so much to gain from exploring the opportunities in proteomics and metabolomics, some serious challenges remain—even when it comes to assessing the data. As Dhungana noted, the ’omics “literature is plagued by irreproducibility, poorly designed studies with insufficient sample sizes, and attempts to translate a marker that is not very stable or robust.”

Analyzing infections

Scientists face a formidable task to explore even one person’s proteins, because there are about 10 billion of them, according to Hanna Budayeva and Donald Kirkpatrick of Genentech. Still, it’s worth exploring these molecules and what they do, because Budayeva and Kirkpatrick wrote: “As drug development progresses against the next generation of challenging targets, understanding the interconnected protein communities that they participate in is critical.”

The entire world sees right now how critical proteomics might be as every country battles COVID-19. To help researchers around the world study this virus, scientists in China developed the 2019 Novel Coronavirus Resource (2018nCoVR). According to this resource’s developers: “2019nCoVR features comprehensive integration of genomic and proteomic sequences as well as their metadata information from the Global Initiative on Sharing All Influenza Data, National Center for Biotechnology Information, China National GeneBank, National Microbiology Data Center and China National Center for Bioinformation (CNCB)/National Genomics Data Center (NGDC).”

The fast pace of the spreading infection requires fast-paced science to stop the virus. For example, one research team used bioRxiv to quickly publish a protein-protein interaction map for SARS-CoV-2—the agent that causes COVID-19. This large team of researchers—with scientists from France, the U.K., and the U.S.—expressed 26 COVID-19 proteins, identified the human proteins that interact with the virus-related proteins, and used that information to identify 332 high confidence SARS-CoV-2-human protein-protein interactions.

“Among these, we identify 67 druggable human proteins or host factors targeted by 69 existing FDA-approved drugs, drugs in clinical trials and/or preclinical compounds, that we are currently evaluating for efficacy in live SARS-CoV-2 infection assays,” the researchers noted.

This work alone reveals the life-saving potential of translating proteomics research to the clinic.

Metabolomic medicine?

Already, scientists apply metabolomics to many basic questions in research as well as health-related ones, but is it ready for the clinic? To find out, I asked Annie Evans, director of R&D at Metabolon. “One of the unique characteristics of metabolomics is its ability to reveal functionality,” she said. “This is of great benefit as it can help to fill the gaps of other ’omics where insights may be lacking.” She added that scientists can use metabolomics to “provide a bridge with other ’omic approaches to more completely understand disease manifestation and state of the phenotype in the present time.”

Annie Evans
Annie Evans
director of R&D, Metabolon

Getting metabolomics into healthcare, though, will take some time. “There is a lot of work ahead of us to make widespread use of clinical metabolomics a reality,” Evans noted. “The exciting aspect of this work, and why I want there to be a day where all people can have their metabolic profile mapped, is that through this work, we are revealing a wealth of new, meaningful, and actionable information that is shaping our understanding of human disease and treatment, or precision medicine.”

Much of the benefit of metabolomics comes from the breadth of what it can reveal. “Metabolomics provides an assessment of health, whether influenced by genes, the environment, epigenetics, or the microbiome, delivering insight into cause and remediation of disease,” Evans said. “For more than five years, Metabolon has been analyzing the metabolomic profiles of individual patient samples, working directly with clinicians and comparing patient data to established healthy cohorts.”

This work in clinics already provides some real-world health benefits. An example Evans noted was “instances where an individual’s metabolic profile showed that they were not tolerating or processing prescribed medications, indicating that changes were needed to prevent long-term damage.” So, this metabolomic information can be used to help a clinician adjust a patient’s treatment. Work at Metabolon also exposed “cases where the metabolic profile indicated that supplementation would potentially lead to improved quality of life,” Evans said. “These are examples of the profound ways clinical metabolomics can deliver precision medicine to help address and influence human health assessments.”

This global metabolic pathway signature from a patient with the rare disease phenylketonuria (top) and the exact biochemical pathway affected (phenylalanine metabolism, bottom) demonstrate how the elevated phenylalanine due to PKU results in the excess production of phenylalanine-associated microbiome metabolites that further support the PKU phenotype in the patient. CREDIT: Metabolon

Although Evans called those the more dramatic examples, she also indicated that metabolomics could provide many details about an individual’s day-to-day life. This information, she said, “can reveal whether people are being exposed to pesticides even though they eat only organic produce or the intensity of their last workout.”

Some of the most interesting information from metabolomics could involve the unknown. As an example, Evans said that Metabolon has been collecting and analyzing patient samples to better understand the role metabolomics plays in health and how it might be used in more instances in the clinical setting. “Some of our findings have led to answers, directional clues, or biomarkers for patients with difficult-to-diagnose diseases that previously had none,” she added.

Metabolomics is also at the heart of exploring the microbiome. “We can go beyond identifying what organisms are in the microbiome to explaining what they are producing,” Evans said. “The impact they are having on the host is illuminated by identifying the metabolic function of the microbiota species and what is crossing over from the gut, mouth, skin, et cetera, and entering into other systems of the body.”

Exploring the endpoints

Even as genomics continues to dominate much of the biological and medical literature, researchers know there is much more to understanding human health than just the effects of our DNA. “Metabolomics and lipidomics are exciting because they are the endpoint readouts of biological processes,” Dhungana said. “They are downstream of genes and proteins, and thus, closer to the phenotype. Measuring the metabolites or lipids truly gives us insight into the biochemical state of a system.”

To really understand how metabolomics impacts an organism, scientists must think broadly. “We now know that both internal processes and external exposure—chemical, microbiome, food—alter the metabolome and contribute towards the phenotype,” Dhungana stated. “This makes it very exciting as we can develop a holistic view of a disease or a condition using metabolite and lipids as our gauges and start asking complex biologically-relevant questions.”

To answer those questions, scientists need to know what metabolites and lipids a person is producing and how much of them. Today’s technology can also reveal the location of these metabolites and lipids. “For example, if we are looking at tumor metabolism, we can measure the metabolites in and around a tumor micro-environment and generate a spatial distribution profile of metabolites or lipids to better understand the metabolic gradient across the tumor and biochemically map the tumor boundaries,” Dhungana explained. Using desorption electrospray ionization (DESI) mass spectrometry (MS), scientists can “spatially visualize the metabolites and lipids from cross-sections of biological tissue samples,” he said. “DESI imaging is in fact a metabolic phenotyping approach as it provides non-subjective information about the biochemical distribution of molecules after just one measurement without any need for labeling.”

Consider a sample of a tumor. “With DESI imaging, one can map the spatially distributed lipid profile within tumor tissue samples and make a non-subjective classification of tumor and tumor boundaries using molecular ion information to complement current histology-based classification techniques,” Dhungana explained. “If the tumor is treated with small-molecule drugs, one can visualize the distribution of those drug and drug metabolites across the tumor with the data collected from the same experiment.”

Technological progress

The top choices in technology for proteomic and metabolomic studies also depend on the challenge. As Winston Timp of Johns Hopkins University and Gregory Timp of the University of Notre Dame described, a variety of sequencing and microscopic techniques can be applied to proteomics. As they wrote, however: “With the advent of scalable, single-molecule DNA sequencing, genomics and transcriptomics have since propelled medicine through improved sensitivity and lower costs, but proteomics has lagged behind.”

In general, advancing metabolomic and proteomic research to the point of broad use in healthcare will certainly require improvements of many kinds. Sometimes scientists and clinicians “need state-of-the-art technology or a novel approach to probing biology,” Dhungana said. “At other times it might be a clever, high-throughput method that reproducibly measures relevant metabolic markers.” Consequently, gaining clinical use from proteomics and metabolomics will depend on developing the needed balance of available technology and using it in the most effective workflows.

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