What is Metabolomics?



Metabolomics is a research method that imitates the research ideas of genomics and proteomics, quantitatively analyzes all metabolites in an organism, and finds the relative relationship between metabolites and physiological and pathological changes. It is an integral part of systems biology. Most of its research objects are small molecular substances with a relative molecular mass of less than 1000. Advanced analysis and detection technology combined with computational analysis methods such as pattern recognition and expert systems is the basic method of metabolomics research.

Metabolomics is a newly developed discipline after genomics and proteomics, and is an important part of systems biology. Since then, it has developed rapidly and penetrated into many fields, such as disease diagnosis, pharmaceutical research and development, nutritional food science, toxicology, environmental science, botany and other fields closely related to human health care. Genomics and proteomics explore the activities of life at the gene and protein levels respectively, but in fact many life activities in cells occur at the metabolite level, such as cell signaling, energy transfer, and intercellular communication. is regulated by metabolites. Metabolomics is the study of the metabolome—the collection of all metabolites in a cell at a time. Genes are closely related to the expression of proteins, while metabolites reflect more about the environment in which cells are located, which are closely related to the nutritional status of cells, the effects of drugs and environmental pollutants, and the influence of other external factors. Hence the argument that “genomics and proteomics tell you what might happen, and metabolomics tells you what did happen.” (Bill Lasley, UC Davis)
The concept of metabolomics comes from the metabolome, which refers to all the low molecular weight metabolites of a certain organism or cell in a specific physiological period, while metabolomics refers to all the low molecular weight metabolites of a certain organism or cell in a specific physiological period. A new discipline for simultaneous qualitative and quantitative analysis of low molecular weight metabolites (Goodacre, 2004). It is a branch of systems biology based on group index analysis, using high-throughput detection and data processing as the means, and aiming at information modeling and system integration.

The concept that individuals might have a “metabolic profile” that could be reflected in the makeup of their biological fluids was introduced by Roger Williams in the late 1940s, who used paper chromatography to suggest characteristic metabolic patterns in urine and saliva were associated with diseases such asschizophrenia. However, it was only through technological advancements in the 1960s and 1970s that it became feasible to quantitatively (as opposed to qualitatively) measure metabolic profiles. The term “metabolic profile” was introduced by Horning, et al. in 1971 after they demonstrated that gas chromatography-mass spectrometry (GC-MS) could be used to measure compounds present in human urine and tissue extracts. The Horning group, along with that of Linus Pauling and Arthur B. Robinson led the development of GC-MS methods to monitor the metabolites present in urine through the 1970s.

Area of ​​research
Metabolomics mainly studies small molecule metabolites (MW<1000) that are substrates and products of various metabolic pathways. In the field of food safety, the use of metabolomics tools to discover relevant biomarkers in animals and plants such as pesticides and veterinary drugs is also a hot field. The samples are mainly the extracts of cells and tissues of animals and plants. The main technical means are nuclear magnetic resonance (NMR), mass spectrometry (MS), chromatography (HPLC, GC) and chromatography-mass spectrometry. By detecting the NMR spectra of a series of samples, combined with pattern recognition methods, the pathophysiological state of the organism can be judged, and it is possible to find the biomarkers associated with it. Provide a predictive platform for relevant early warning signals.

Development history
The emergence of metabolomics is inevitable in life science research. Metabolomics, developed in the mid-1990s, is a new discipline for qualitative and quantitative analysis of small molecule metabolites with relative molecular weights less than 1,000 in a certain organism or cell. As an important part of systems biology, the metabolome has broad application prospects in the field of clinical medicine.

Metabolites are the final products of gene expression and are generated under the action of metabolic enzymes. Although metabolites are small compared to genes or proteins, cells that cannot form metabolites are dead cells, so the importance of metabolites cannot be underestimated.
Researchers can judge whether the body is in a normal state by in-depth study of the body’s metabolites, while the study of genes and proteins cannot draw such a conclusion. In fact, metabolomic studies have been able to diagnose some metabolic diseases, such as diabetes, obesity, metabolic syndrome. Currently, well-studied common metabolic pathways include the tricarboxylic acid cycle (TCA), glycolysis, and arachidonic acid (AA)/inflammatory pathways.

Research methods
The research methods of metabolomics are similar to those of proteomics, and there are usually two methods. One method, called metabolomic fingerprinting, uses liquid chromatography-mass spectrometry (LC-MS) to compare individual metabolites in different blood samples to determine all of them. Essentially, metabolic fingerprinting involves comparing the mass spectral peaks of metabolites in different individuals, ultimately understanding the structure of different compounds, and establishing a comprehensive set of analytical methods to characterize these different compounds. Another approach is metabolic profiling, in which researchers postulate a specific metabolic pathway and study it in more depth.
For metabolites, it is not only the characteristic of mass spectral peaks. Furthermore, mass spectrometry (MS) cannot detect all metabolites, not because MS is not sensitive enough, but because MS can only detect ionized species, but some metabolites cannot be ionized in a mass spectrometer. The use of nuclear magnetic resonance (NMR) methods can make up for the lack of chromatography. Dr Jules Griffin, of the University of Cambridge, is using a combination of mass spectrometry and nuclear magnetic resonance to try to build a complete map of metabolic pathways in the body. Griffin uses nuclear magnetic resonance to detect high-abundance metabolites. Due to the low sensitivity of nuclear magnetic resonance detection, it is only used to analyze low-abundance metabolites.
In the past, only toxicology studies have used NMR, and mass spectrometry has only been used in plant metabolism studies. Today, these two methods are commonly used in metabolomics research. To make meaningful comparisons between different samples, researchers must combine the large amounts of data obtained using both methods. In addition, data from genomics studies need to be combined.
Dr. Gary Siuzdak, who studies bioinformatics problems at The Cripps Research Institute (TSRI), designed an experimental protocol to analyze changes in metabolites from different samples. Researchers can identify metabolites by comparing the different data with the bioinformatics software XEMS. The software provides molecular weight data for all metabolites whose concentrations vary from individual to individual. The data is freely available to the public online.
Dr. Siuzdak said they are taking an integrative approach to metabolomics, trying to detect as many metabolites as possible beyond what people have been able to achieve using methods in the past. Through individual studies, it is hoped that new molecules may be identified to some extent associated with stress, which could be a disease, a knockout of an enzyme, or something else.

Metabolomics as a new generation omics technology driven by systems biology in the post-gene era, its core value is to elucidate all key scientific issues related to cell metabolism by qualitatively describing and quantitatively characterizing small molecule metabolomes in different biological matrices. Furthermore, we can understand different biochemical processes and biological events from the metabolic dimension, such as disease occurrence/diagnosis, drug action/toxicology, nutritional health/intervention, plant physiology/pathology, microbial infection/treatment, environmental toxicology/ Repair, genetic mutation/modification, etc. However, in the past decade, the development of metabolomics, like other Life-Omics, has faced a huge dilemma.
Due to the limitations of our existing technical means and biochemical cognition, at present, omics research is still at the level of high-throughput collection and preliminary analysis of phenotypic data, which we define as Phenotypic Metabolomics. To truly solve the above-mentioned key scientific problems related to metabolism, functional metabolomics research (Functional Metabolomics) is imperative.

Disease diagnosis
Compared with genomics and proteomics, the research of metabolomics focuses on the commonality of specific components, and ultimately involves the study of the commonality, characteristics and laws of each metabolic component, which is currently far from the goal. Despite its challenges, researchers remain convinced that metabolomics is more closely linked to physiology than genomics and proteomics. Diseases lead to changes in the body’s pathophysiological processes, and eventually lead to corresponding changes in metabolites. By analyzing some metabolites and comparing them with normal people’s metabolites, looking for biomarkers of disease will provide a better disease diagnosis method.

Medical application
Metabolomics researchers have studied this. Whether a newborn is missing the enzyme gene can be detected at birth. Detectables include enzymes involved in building blocks of synthetic pathways, such as amino acids. The result of enzyme deficiency is too little or too much of the corresponding metabolite. Phenylketonuria (PKU) is a common infant disease. The disease is caused by the accumulation of phenylalanine in the blood due to the deletion of the phenylalanine hydrolase gene, which is necessary to hydrolyze phenylalanine into tyrosine. This innate metabolic deficiency, if not detected in time, can cause irreversible brain damage within nine months of birth. The disease can be diagnosed with a simple blood sample and a urea test. The blood and urea assays will also become part of the metabolic fingerprinting methodology in the future. In diseases like phenylketonuria, researchers are trying to start with the biochemical basis of the disease, rather than just testing for biomarkers. They hope that through metabolomics, better ways to treat these diseases can be found.

Expert testimonials
Dr. Siuzdak is optimistic and realistic about metabolomics. “Metabolomics is still in its infancy,” he explains, and if we can understand 5-10% of metabolites, we’re lucky. Considered this way, the reality is that we still know nothing about the role of these molecules. However, it is believed that with the continuous improvement and optimization of its methods, metabolomics research will surely become a powerful means for human beings to diagnose diseases more efficiently and accurately.