The 'ome' and `omics', of biology

AS A field of knowledge develops and fundamental principles, laws and connecting themes are unravelled, the business of naming ideas, rules, basic units and so forth starts roaring. The first rage in this naming game in physical sciences was with the suffix "-on". When it was discovered that substances can have electrical charges in them, the field of electricity developed rapidly. About two hundred years ago, people began talking about measuring electrical charge, current and force. Soon enough it was recognized that the smallest (fundamental) electrical charge can be associated with a particle - and based on the Latin word electrum for amber which was electrically charged when rubbed - it became christened as the electron. The suffix "on" here is a borrowing from Greek, and became the standard appendage for a variety of related fundamental particles. Hence the proton, neutron, positron, meson, baryon, lepton, hadron and so on. Even light has its photon, and sound its phonon. Study of the `on' and its application came to be termed as "-onics", for example electronics. The topic dealing with electronic applications in aviation is avionics and in biological machines bionics.

Chemists soon took on the trend and called an electrically charged molecule or its fragment simply an "ion", and a basic molecular unit out of which more complex ones are built as a "synthon". Biologists were not to be left behind. When it was discovered that genes are read and transcribed and translated into proteins on the basis of code words put together as three- base-long sequences of the DNA chain, they promptly dubbed the 64 fundamental words of the genetic vocabulary as "codons". When they found that strings of these words can move across and transpose themselves within chromosomes in a cut-and-paste manner thereby altering the genetic messages, they named these moving gene phrases as "transposons".

Then came the "-ome"

Next came the suffix "-omics". While "on" is for the fundamental individual unit or particle, the "-ome" refers to an abstract entity, a group, an aggregate or a collection. A study of the "ome" is quantitative, is an analysis of the numbers involved and a look at the interaction among and between collections. The field focusing on such a collection becomes "-onomy" (from the Latin to understand, to manage; examples: astronomy, agronomy), and is more rigorous than the "ology" (meaning study, example: astrology). The "-onomists" and the "-onomers" think of themselves as a cut above the "ologists" and "-ologers". (May I beg the pardon of ecologists, who are a different class? As for topologists, there are no toponomers or toponomists, only topographers!). The quantitative study of a field is often dubbed "-omics" and thus economics and agronomics.

As my discerning readers have already guessed, this prelude takes us to the current excitement in biology, namely genomics - the study of the entire collection of genes in an organism. Dr. John Weinstein of the National Cancer Institute, USA, wrote over two years ago (Science, 23 October 1998) that such "omic research" is not just a fishing expedition or a random attempt, but one that demands a different mindset from the more traditional study of a single gene, gene product or process at a time. It should be viewed as synergistic with the more traditional studies of single molecules. As an example, Weinstein points to the area that has come to be called as ecogenomics, which looks at the differences in the responses of individual humans (or other organisms) to environmental agents and influences. These differences arise based on factors in the body chemistry, which can differ among individuals based on minor variations in their genes. The response itself is there but differs in minor ways; thus it is not a mutation, which is more drastic. Hence it is referred to as genetic polymorphism, namely the variation in the constitution and the way the genes are assembled and interact. Analysing such polymorphism involves a direct comparison of the genomes of the individuals, and does not demand an advance knowledge of which genes or factors cause the differential response. The traditional approach studies the genes of individuals one at a time, makes a tabulation of who are `normal' and identifies the ones who respond differently. Genomics differs from such one-at-a-time individual genetic analysis and does it from a mass perspective. It is like the shepherd who takes snapshot looks at the dozens of his sheep marching as a herd and picks out the limping ones. Or like how a parent penguin returns from the sea and picks out her awaiting baby from amongst the thousands herded together on the shore. It is not a one-by-one analysis, but a pick from a collection present all at once.

Straight genomics, adjectivised genomics and the Indian Railway System

As the DNA sequences of entire genomes (the total collection of genes in the chromosomes) of various organisms - viruses, bacteria and fungi, parasites, worms, flies, plants, animals and humans become available, we should like to use these oceans of genetic information in order to make sense out of them. We need to know how to read the sequence, to identify the genes and understand what function each of them performs. "Mining" of such encyclopediae is a sub-discipline in itself called bioinformatics. (Here is another suffix, "-matics", a la mathematics or numismatics, denoting in this case analysis, classification, and pattern-deriving exercises from biological information. The most commonly used data are sequences of amino acids in protein chains, or bases sequences in RNA and DNA, atomic coordinates relating to the shapes and structures of biomolecules and the like). Practitioners of this field often do in silico exercises (using processors made of silicon chips fitted inside digital computers, hence the phrase), replacing or complementing experiments that biologists do in vivo (using live organisms or their living parts - viva refers to life) or in vitro (using biological molecules or assemblies in glass test tubes - vitro refers to glass, though more often these days they work with plasticware - in plastico?).

Such exercises are needed to make sense out of the enormous body of information contained in the genome sequence. In silico analyses of these genomic data tell us about the number and sequences of genes. In the case of the human genome, whose draft sequence was announced with great excitement seven months ago, we still need to figure out how many genes there actually are. That might take a year or so. But even then, it will only be the beginning, not the end, the gunshot denoting the start of the marathon and not the finish-line tape. And it will be straight genomics, or an enumeration of the numbers and sequences of all the genes in a typical healthy human.

Turning this genomic information into usable biochemical or physiological information is a bit like navigating the Indian Railway System. Straight genomics will have listed out the names of all the stations, but not tell us how they connect with one another. Understanding how they are connected, and how and when these train stations become active with train traffic is the task of functional genomics. Functional genomics tries to determine how, when and where genes act, through the proteins that they encode, inside the body. Much of this exercise will have to be done by laboratory "wet" experiments, not just in silico. The field is flush with excitement due to the development of new strategies; there are already four different approaches, all within the last two years, devised to figure out the working of the genome, termed transposon tagging, RNA interference, chemical switching and multiple hybrid assay.

There is a related technique that analyses not the genes but gene products, namely proteins. One takes an extract of a chosen tissue or cell, collects all the proteins in it and separates them into individual spots in a gel, using an electrical field. Comparison of the 2-dimensional pattern of the proteins so obtained with that of a standard gel helps in identifying which proteins are present (or absent, or modified) in the extract, and gives an idea of which genes are expressed, silenced or modified in the tissue or cell. This all-at-once analysis of the proteins is called, you guessed it, proteomics.0

The typical and the individual

What has been made available seven months ago is the draft of a representative, standard or "typical" human genome. In order that it is useful for a specific individual, say myself, I need to know my own or personal genome sequence. Comparison of my genome sequence with that of the "standard" one would let me know which of my genes are the same and which are different. Usually, some bit of differences in the gene sequences is tolerated and does not affect its function; at best it might tell as a slight variation in biochemical response and classified as due to genetic polymorphism (literally multiple forms). Occasionally, even a minor difference in the sequence can lead to crucial changes in biochemical and physiological responses, even disorders. Such a drastic deviation or sequence error is termed a mutation. Since it occurs in genes and genes are transmitted from parent to progeny, such mutations tend to run in families, and become part of the inherited traits. For example, mutation in a single codon in the gene for the blood protein globin makes the carrier individual suffer from anemia.

On the other hand, even a couple of changes in some other codons is tolerated and leads at best to minor physiological changes. An oft- quoted example of such genetic polymorphism is the case of several Japanese men and women who are not able to handle more than one glass of sake or wine. Minor alerations in the gene for one of the alcohol-metabolizing enzymes in the individual makes them go flush red in face and suffer a while, until the excess alcohol is flushed out of the system. This is an example of a more general phenomenon where a given amount of a substance (typically a toxin, allergen or a drug) evokes different reactions in different individuals. For example, some people break into rashes and great discomfort when given the antibiotic penicillin, while others tolerate and benefit from it. A caring and knowledgable doctor inquires first whether the patient is allergic to any drug before he writes the prescription and, where necessary, advises alternate medication.

Individual tolerances and reactions to the type and dosage of drugs arising out of genetic polymorphism have been formally recognized, leading to yet another "omics", this one called pharmacogenomics. The ultimate idea here is to translate functional genomics into rational therapeutics. Polymorphism accounts for different abilities between individuals in metabolizing drugs such as anti-depressants, beta blockers, or even anti-inflammatory substances such as ibuprofen. The enzymes involved are abbreviated as CYP2C9 and CYP2D6. Likewise, sequence polymorphism in the gene for the protein called P-glycoprotein leads to differences in the ability of individuals in being able to transport certain drugs into their cells, while that in the gene for proteins such as P53 or ALL leads to variable response to anticancer drugs.

Gene passports?

The ideal situation would be to be able to know what genes (or gene products) in me respond to which drugs in what ways. Some clever developments in the field of genomics let us approach this Herculean task with relative ease. The technology of DNA-Chips or Gene Cards makes this possible. In making such a chip, a set of chosen genes (or parts of genes, say CYP2C9, P53, ACE, and so on) is chemically attached to a quartz plate in a geometric array, making a two dimensional comb, each tooth a given gene. (This is somewhat akin to the etching of electrical circuits by photolithography on a silicon chip, to make computer processors, and hence the name DNA Chip). If I need to know whether these genes are normal in my body or whether I am genetically prone to adverse reaction to certain drugs that modulate these genes, I take the relevant cell extract from my body and immerse the DNA chip in it. Depending on the manner and extent in which the material in the cell extract (actually the RNA produced in my body from these chosen genes) sticks to the DNA in the chip, my pathological and diagnostic picture is revealed. Custom-made or individual- specific drug prescription and therapy! The Nobelist Walter Glibert (who devised a way to read the base sequences in DNA) anticipated such developments a couple of years ago. He is reported to have said that the time is not far off when each of us, if we so wish, can carry a personal DNA Card of our own, in much the manner that we carry bank credit cards or passports. This would contain chosen genes from our own genomes, and we can take it to the pharmacist and get the drug best suited to our physiological condition! Such a personalized DNA Card can help us in other "omics" as well, such as immunomics (genomics related to the immune status of the individual), toxinomics (study of the interaction profiles of toxins with genes in the genome), metabolomics (focusing genomic study on chosen metabolic paths, helpful in understanding factors relating to nutrition, ageing, obesity and so forth), ethnogenomics (relating to the ethnic origin of the individual) and the like.

Yesterday's fiction is today's reality - recall how, as youngsters, we read how the hero Dick Tracy wore a special wrist band that not only acted as a remote sensor of dangers and challenges ahead, but also the status of his own preparedness to meet them? That belonged to the era of another "omics", namely the comics!

D.Balasubramanian L. V. Prasad Eye Institute Hyderabad- 500 034

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