Metabolomics can explain:

• The mechanisms that are responsible for metabolite level changes in cells and whole organisms.
• How these changes in metabolite levels relate to disease conditions and the intake of drugs.
• Metabolomics can apportion the role of nutritional factors, environmental factors and genetic factors on disease susceptibility and its progression.

As metabolomics denotes a systems approach to biology, it means understanding the metabolites that are produced in very complex biochemical pathways. This would help us understand how a disease progresses and what possible treatment could be provided. An individual's diet has a considerable impact on the duration of his lifespan and the build-up of resistance to disease. Metabolomics can be used to evaluate this aspect too.


Reason why metabolomics is used in drug research


Time and money constraints including the disparity between the costs involved in researching for a new drug and the possible returns it could generate in monetary terms impede the discovery of new drugs for serious illnesses that affect plenty of people. A possible solution to this is to quickly identify a new molecule that if developed further could become successful. Metabolomics can help in this.


Usually the obvious method of testing drugs is to first test them on cells, then animals and finally in humans. But this is a lengthy process and will not be suitable at the screening stage of drug discovery. One method is to screen drug candidates under review in "in vitro" cells and tissue, in order to get a correct perspective of the pharmacological attributes of the compound. The other is to evaluate the effect of the drug on biochemical pathways of living cells perhaps using analytical and computational methods. During that process different metabolic pathways produce metabolites ---- and by analyzing these metabolites, a decision is taken whether to research the medicine further or not.


These metabolites could be glucose or organic substances including amino acids. The concentration of these metabolites which are usually small molecule intermediary products or the changes that occur in their content is indicative of how a metabolic pathway behaves in response to a new drug or some other external factor or environmental factor. Thereafter one has to decide on the basis of the regulatory role of the metabolic pathways that are responsive to the administration of experimental drugs.


An example

The administration of rosiglitazone has resulted sometimes in decreased triglyceride and cholesterol levels. This probably means that the drug blocks the flow of fresh lipid synthesis. But researchers have found that rosiglitazone leads to excess fat in the liver and causes acute toxicity. What this probably means is that metabolomic investigations of several metabolites are essential in designing drugs to facilitate proper lipid metabolism.


How metabolites are evaluated in a given biological sample?


NMR and MS are the key analytical tools used in metabolomic studies. A brief explanation of the two follows.

NMR

How a metabolomic experiment is conducted using NMR? The biological sample as for example urine or plasma or in some cases the solvent extract of the biological sample is first placed in a magnetic field. Then this sample is subjected to radio-waves within a specified frequency. How this sample absorbs energy is indicative of the quantum of metabolites present. So the researcher gets an NMR spectrum pertaining to the metabolic profile of the sample. This can be compared to the NMR spectra of other biological samples being referenced

MS

The other method is MS. How is this carried out? MS has the capability to separate compounds on the basis of molecular mass. So to do the assay, a sample is injected into MS and as output you get a listing of molecular masses of compounds present in the sample. Thereafter the metabolite is identified corresponding to their prominence in the sample and in accordance with their molecular mass. MS can identify the presence of small amounts of metabolites and is more sensitive than NMR.


Metabolomic approach in evaluation of Disease Conditions

As compared to transcriptome or proteome, the metabolome is the closest to cell state and therefore variations in the metabolome is representative of disease progression. Hence metabolomic analysis can help tell us about the following:
How new medications behave in the body
Nutritional deficiencies
The genetic predisposition

Here are a few examples relating disease conditions with metabolomics

In Huntington's disease

As compared to genomic, transcriptomic, and proteomic methods metabolomic approach can give a whole picture-----and together they complement each other. For example if a gene that is indicative of a particular disease is present, it doesn't necessarily mean that disease is manifest or present. However for the disease symptoms to occur, other biological information has to be evaluated. For example, if a certain variant of a gene relating to Huntington's disease is present it means the possibility of neural degeneration. But one can't say when the symptoms will occur. If a predisposing genetic variant indicative of a disease is present, then it will be juxtaposed with altered blood metabolite patterns to reach a decision. That is how metabolomics can help. Similarly in alcohol dependence it is not a single gene that is a causative factor. So data pertaining to several genes is integrated with transcriptomic, proteomic, data


In Leukemia

Leukemia cells have the following features:
Glucose uptake is on the higher side
Overactivity of the enzyme hexokinase
In the pentose phosphate pathway, the oxidative branch is found to be overactive.

All of the above factors help in the synthesis of nucleic acids that are essential for the multiplication of leukemia cells. The drug Gleevec inhibits the above processes----so nucleic acids don't get formed. But sometimes the tumor cells develop resistance to Gleevac. This happens because the cells enhance the activity of pentose phosphate pathway's non-oxidative branch----that is not appreciably inhibited by Gleevec. Therefore, following the administration of Gleevac it is necessary to quantitatively assess different metabolic pathways. Such a systems approach to bioanalysis is made possible by metabolomics. In the case of Gleevac it is necessary to assess the pentose phosphate pathway in terms of downregulation of the oxidative branch and simultaneous upregulation of the nonoxidative branch. The differentiation between pentose phosphate pathway's glucose metabolism as occurring through its oxidative and non-oxidative branches can be done through proprietory SIDMAP analysis



In megaloblastic anemia


Thiamine-responsive megaloblastic anemia is a blood disorder. A patient with TRMA has deficient transketolase activity. This impedes nucleic acid synthesis and results in deficiencies in the cells normal cycle of functioning. But now using metabolic flux analysis we can co-relate it to drug mechanisms and disease.Metabolomics can be used to understand how a disease progresses and also in developing medicines.


In atherosclerotic lesions

Macrophages have a role to play in the making of atherosclerotic lesions. If changes in macrophage biology could be interpolated with changes in lipid metabolism----it could help in discovering new drugs.


Research Initiatives

Although advances in biochemistry have helped us understand the etiology of disease mechanisms, if specific metabolites and metabolic pathways can be understood better it would be possible to prescribe treatment methodology on a personalized basis. The NIH Roadmap Initiative and the NIH Genes, Environment and Health Initiative are two instances of how metabolomic evaluation could help in researching diseases further.


The NIH Roadmap Initiative

This initiative is the result of the recognition of the fact that in future the development of new drugs will depend upon the quantitative analysis of the molecules that make up our cells and tissues and also how they interact and regulate biochemical pathways. In other words we need to know the molecular basis of disease progression. In order to achieve this, access to interconnected data bases are essential for the researcher. So this initiative aims to provide chemical molecule libraries that facilitate:
• Imaging probes for molecular/cellular events occurring in bio-networks;
• Providing advanced computational facilities for metabolic research.
• Suggesting targets for developing new medical treatments.
• Providing nanotechnology instrumentation for seeing rudimentary cellular processes.


NIH Genes, Environment and Health Initiative

The aim of this initiative is to measure the environmental factors responsible for disease progression and also to reckon with the genetic factors that cause diseases. That apart the aim is to juxtapose research findings to what happens in clinical situation.

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