Defined as the small molecules that make up biological systems and are present in biofluids or tissues, metabolites can be indicative of not only the internal factors related to disease but also the contribution of external factors, such as environment and lifestyle. Metabolomics, the study of metabolites and their interactions, can provide insight into an individual’s current health status and disease predisposition. Other applications include the use of metabolites as biomarkers, for disease treatment and monitoring, for patient stratification in clinical trials and for drug development.
Metabolic phenotyping is the comprehensive, simultaneous profiling of the metabolites in a sample. Utilizing LC/MS and NMR, researchers can identify and quantify the hundreds to thousands of metabolites found in a single sample. The techniques are complementary as LC/MS provides high sensitivity, while NMR is nondestructive and highly reproducible.
Launched earlier this month, the International Phenome Center Network (IPCN) is a new international effort aimed at advancing the development and use of metabolic phenotyping for phenomics, the study of the interaction of genes and the environment. The IPCN has announced seven centers so far (see table below). Each center will be self-funded, but the IPCN will be overseen by a steering committee consisting of a representative of each member.
Among the founding members are instrument suppliers Bruker and Waters, which will provide technical support and development for NMR and LC/MS, respectively. Specifically, Waters will work to develop technology and methodology, as well as provide training for IPCN researchers, which will take place at an existing facility at Imperial College currently staffed by Waters employees.
Bruker will provide technical support and development for NMR for the IPCN. “The opportunity for NMR is to contribute to the big quest for precision health and, there in, metabolic phenotyping is a key element in prediction, prevention and curing,” commented Iris Mangelschots, PhD, president of Bruker’s AIC (Applied, Industrial and Clinical) Division at Bruker.
The IPCN is coordinated by the UK’s Medical Research Council (MRC) and National Institutes of Health Research (NIHR)– sponsored National Phenome Centre, one of the world’s largest metabolomics centers.
Founded in 2013, the National Phenome Centre, in which Bruker, Waters and Imperial College London are partners, is focused on both targeted and nontargeted metabolomics for biomarker and population-based studies, including the development of methods and standards. It has received a funding commitment of £10 million ($15 million = £0.65 = $1) over five years from the UK government.
The IPCN builds upon the work of the National Phenome Centre. As Rohit Khanna, PhD, senior vice president of Waters’ Applied Technology Group, told IBO, Waters’ work with the Centre has led to advancement in LC/MS hardware and software for metabolic phenotyping. A focus of the partnership has also been the development of LC/MS standards and methods for metabolic phenotyping. “A lot of work has been done [at the National Phenome Centre] to standardize methodologies to be able to do large-scale population analysis: to run that number of samples through the LC/MS systems and to correlate the data. To do this consistently was critical,” noted Dr. Khanna. “I think the work that has been done over the first few years has allowed us to put that standardization in place.” With the IPCN, these standards, methods and technology developments will now be applied to larger sample sets.
Bruker’s work with the National Phenome Centre also involved the development of methods and standards for NMR for metabolic phenotyping. Describing the benefits of standardized and harmonized methods for the IPCN’s multiple centers, Dr. Mangelschots told IBO, “Because we are working within a controlled NMR measuring set, which is described in our SOP, [the centers] can easily exchange data; exchange data for doing similar studies, but on a much larger amount of samples, or even changing disciplines,” she said.
In addition, Bruker’s partnership with the Centre has led to technical developments, including technology focused on sample preparation for NMR. Manfred Spraul, PhD, CTO of Bruker BioSpin’s AIC Division, described the development of an automated sample preparation system to keep tissues cool prior to analysis “[So when] we want to run something like 500 to 600 samples in one go on a sample changer, we need cooling.”
In addition to the application of standards and methods to higher volumes, the IPCN’s global presence is also a key development. As Dr. Mangelschots explained, an international focus is essential to advancing the field. “There are IPCN members at different physical locations from a geographical perspective, so they have access to biosamples from different regions,” she noted.
In particular, the IPCN will benefit from uniquely large data sets, which allow for improved correlation of metabolites with disease states, human health and environmental factors. “With rare exception, there are only a couple of centers globally that are working at this level of volume,” explained Dr. Khanna. “Before the IPCN, few labs existed with the capacity and size of investment in metabolomics to run such large-scale samples. To the volume that we are talking about, which is tens of thousands of samples, you need a large laboratory with large investment and a large number of systems.”
Dr. Khanna told IBO that he expects the IPCN to expand to 10 centers over the next couple of years. Areas of research will be varied, depending on each individual center’s focus. However, certain diseases will be prioritized across all centers. “It hasn’t yet been decided by the network which will be the top three or four initial areas, but I can assume, from my conversation with them, diabetes will probably come up high on the list, autism is one that seems to be high on the list, [and] probably some of the cancers.”
The selection of which centers will participate was designed to represent geographical and disease diversity, according to Dr. Mangelschots. “All the members of the IPCN have strengths in certain clinical questions. This is how they are selected; either they have complementary strengths or have reach within important geographical areas from the biosample perspective.”
For NMR, the capabilities will extend to retrospective testing of samples for other diseases. “I think it is a unique capability of NMR that, once you have a spectrum measured, you can look to cardiovascular issues, and, at the same time, you can look with the same spectrum, you can look into diabetes, hypertension and cancer, for example,” noted Dr. Spraul. “You can stress test new test assays on much bigger data samples, which you might have measured several years ago,” explained Dr. Mangelschots.
For Bruker, the IPCN also advances the clinical promise of metabolic phenotyping using NMR. “We would like our standards to move into a CE- or a 13485- or even an FDA-based platform. That platform would be our system and platform-enabling tools within these SOPs, so that any partner within the IPCN and beyond who is a developing a test can then go into LDT with their assay or even inspire an FDA approval,” stated Dr. Mangelschots.
For LC/MS, Dr. Khanna explained that the IPCN is representative of the technology’s importance to personalized medicine and study of the human phenotype. “Of all the different omics that are going to be necessary, LC/MS is critical in all of those omics with the exception of genomics.” He told IBO, “When someone says personalized medicine, when someone says microbiome initiative, it is within this bigger umbrella of metabolic phenotyping. It all fits together. You have to answer these fundamental questions,” he said. “I think the time is really good right now for this whole industry around the expansion of medical research into phenotyping—into all the different omics areas.”