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Human genome: The DNA sequences of all the genes was deciphered a few years ago.

This catalogue is referred to as, what else, our metabolome. Remarkably, many of these metabolites are the same as what are found in just about every life form on earth- E. coli to the elephant. We inherit our metabolites from the p rimitive life forms of billions years ago.

When the DNA sequences of all the genes contained in our body, our genome, was deciphered a few years ago, the naive belief was that we have read the pages in the book of life, and that it would only take some time before we crack the puzzle of every biological process in our body.

Perceptive biologists knew better. As Dr. Eric Lander said, decoding the genome is akin to writing out the list of parts that make a Boeing 727, and the challenge starts now: to understand how the parts are put together, what each part does, and how they interact and govern each other’s actions. This is the business of the new subject called systems biology.

Note how the description and approach has moved from that of the “nothing but” reductionist (“a cell is nothing but a collection of chemical reactions”) to that of a systems engineer.

The genome of an organism, that is, its full DNA content, is present in most of its cells. Yet, not all of it is ‘expressed’ in every cell. While the islet cells of the pancreas make insulin, muscle cells with the same genome present, do not.

Many of the proteins produced in the islets are different from those in the muscle. While the genome is the same, the ‘proteomes’ in the two cells differ.

The proteome, as can be guessed, refers to the full complement of proteins produced by the genome in a cell. The human proteome is the total collection of all proteins produced by all parts of the human body.

Distinct sets of proteins are produced and used in different cell types and developmental stages. And the proteome in a given cell can differ in health and in disease.

The genome is a relatively less dynamic component of the whole organism, while the proteome describes the dynamics of the various parts of the organism. It is influenced by what goes on inside the cells – growth, differentiation, division, damage, as well as outside the cells – the environment.

Reading the proteome is done by spilling the contents of the cell on a sheet of a polymer gel, passing electric current and separating each protein based on its size and charge.

Interestingly, while our genome has about 30,000 genes (instruction sentences), our proteome is as large as over 1,00,000 (translated pieces). While this gives an idea of the dynamics of the proteome, it poses the puzzle of how and what is gained or lost in translation, and how and why the proteome content of one organ differs from that of another. Turn to the matabolome. This term refers to the complete set of small molecules metabolized found in the organism.

Metabolites are the currency of cells – involved in the normal growth, development and reproduction. While DNA, RNA, and proteins are polymers, each a long chain made of a few basic building blocks strung together, metabolites of small molecules and their total number, as mentioned above, can run to over 7,000.

The metabolome involves a large network of metabolic reactions, most of which are catalyzed by enzymes. The output of one such reaction forms the inputs of other chemical reactions.

These form the metabolic networks that biochemists since the days of Emden and Meyerhoff, or Cori and Cori, David Green, or our own P.S. Sarma, B.C. Guha, and other biochemists have described in great detail. Metobolomics refers to the systematic study of the chemical fingerprints, or metabolic profiles, in the organism. It is even more dynamic then proteomics.

Given that cells and organisms are “open systems”, exchanging material and energy with the environment, metabolomics or quantitative analysis of metabolic profiles during health and sickness is of value.

The new area of systems biology attempts to integrate the genome, proteome and metabolome in order to give a more complete picture of the dynamics of a living organism. In every day life, the clinical diagnostics and pathology laboratory does metabolomics when the technician measures the levels of sugar, urea, creatinine and several other metabolites, all at the same time, in blood or urine. Measuring one of them is incomplete; we need several in order to get a more dynamic picture.

The challenge in metabolomics is just this – measuring often as many as a hundred metabolites at once from a sample.

(Interestingly it was the genius Linus Pauling who initiated this area in 1971, in the name of orthomolecular medicine). This has become possible now with the advent of chromatography and mass spectrometry.

Metabolic profiling of this type is useful to understand the biochemical results of a gene mutation. It also helps us understand, why, for example, a bit of carotene is good for the eye, but excess of it can be carcinogenic. Such profiling has been particularly successful with yeast – an organism with about 5,000 genes, and happily enough almost as many single gene mutants. The Imperial College group at London has exploited this feature of yeast to try and do a systematic functional analysis of the yeast genome (Trends in Biotechnology, September 1998).

As can be guessed, analysis of all the metabolic levels in real time and connecting them with the biochemical network of the organism needs help from bioinformatics, data analysis, and management.

Systems biology is thus a highly interdisciplinary field – genetics and biochemistry, bioinformatics, computer modelling, and data analysis (see the review by V. Shulaev of Virginia Bioinformatics Institute, in Briefings in Bioinformatics, 7, 128-139, 2006). The rewards are rich- giving information on toxicity analysis of drugs, disease diagnosis, metabolic fingerprinting and basic biology.

Here is an area that is still developing, an area where India can take a leading role by putting together biologists, computer scientists, and systems analysts. Lets us go for it.

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