Man is by nature curious. He wants to know about everything, and his own body and its working is no exception. This snoopiness was the driving force behind his creating such scientific disciplines as anatomy and physiology. From 1500 B.C. old Egyptian papyri to the works of Galen, and the discoveries of Neil Harvey to the invention of modern tomography scans, this quest to know about human body is evident throughout recorded history. But now this quest has entered a new chapter, and man is on the verge of cracking the ultimate code of life: the base-by-base mapping of the entire human genome. This multibillion-dollar endeavor, called Human Genome Project, dwarfs such previous gigantic ventures as building of the Pyramids and the Great Wall of China, the Manhattan Project (to build the first atomic bomb) and the Apollo Mission --in both impact and the amount of effort involved in the execution. The project is so ambitious that its full implications are hard to grasp at this time. When successfully completed, it could pave the way for making the 4000 or so known genetic diseases a thing of the past. By opening the treasure trove of information neatly packed into every one of our one hundred trillion cells, the Project also promises to provide valuable insights into myriad biochemical processes that underlie many diseases.

In the words of Eric Lander, director of the Whitehead/MIT Center for Genomic Research, the project could do what the periodic table did for chemistry 150 years ago.

HISTORY OF HUMAN GENOME PROJECT

Date: December 1984

Place: Cottonwood Canyon, near Salt Lake City, USA

A conference was held in this skier's paradise under the auspices of the US Department of Energy to discuss the effects of nuclear radiation on the rate of mutations in the survivors and descendents of Hiroshima and Nagasaki bombings. But very early into the proceedings, it was felt that the undertaking is futile without having the whole genome of a normal person as a yardstick against which the extent of mutations in the radiations suffers could be measured.

After numerous subsequent conferences, meetings, workshops and public debates, a consensus finally developed and the DOE announced its Human Genome Initiative in 1986. Two years later, the National Institute of Health signed a Memorandum of Understanding with the DOE and thus formally stepped into the pursuit.

In the same year, the Human Genome Organization (HUGO) was created in Europe to coordinate research in different parts of the world. The Human Genome Project set sail officially in October 1990. Today, major players in the HGP are the Office of Biological and Environmental Research of DOE, the National Human Genome Research Institute of NIH in the US, and the Sanger Institute of the Wellcome Trust in UK. Apart from these institutes, geneticists, laboratory technicians, chemists, computer scientists and mathematicians from at least 16 countries are taking part in the hunt.

The six feet long thread of DNA is in fact a chord that binds the entire humanity.

WHAT IS A GENOME?

A genome is the complete set of information incorporated in all the chromosomes of an organism. You may recall that a chromosome is a haystack of one very, very long DNA molecule wrapped around the protein molecules. If DNA were a rope one inch thick, the length of the rope would be about 23,000 km, circling more than half way around the world.

DNA itself a twisted ladder composed of small units called nucleotides. Each nucleotide consists of two phosphate moieties, making the backbone of the molecule; two deoxyribose sugar molecules and a base pair. There are four bases in all but only two combinations are allowed: cytosine-guanine and thymine-adenine. It's the order of these bases that makes the alphabet of the genetic jargon. This order does nothing but instructs the cellular machinery to make a certain protein. The base order CG AT GC, for example, codes for the amino acid histidine. The proteins -- composed of chains of amino acids -- perform myriad housekeeping functions in the body. A gene is a long sequence of bases containing codes for various amino acids necessary for the synthesis of one protein.

It has been estimated that the genome contains from 80,000 to 100,000 genes, out of which only 10,000 have been identified so far. These genes comprise only 3% of the genome however; the rest is long, highly repetitious stretches called "junk" DNA. As the name implies, this stretches serve no known purpose.

HGP METHODOLOGY

There are around 3.2 billion base pairs in total in the human genome. The core aim of the Human Genome Project is to first determine the sequence of all these bases, and then put them in order as they occur in the 46 chromosomes. A daunting task indeed. To give you an idea, just imagine this: If the entire base order is written in this magazine without any spaces (and ads!) in the font size you are reading now, an Elixir will result with 14 million pages. If these pages were stacked, they would reach a height of 234 feet! And if somebody tries to recite this magazine, day and night, the undertaking would take 11 years.

HOW THE MAPPING IS DONE

The work on mapping the genome started much before the ribbons were cut for the HGP less than a decade ago. It was observed in the early years of the 20th century that the gene for color blindness was passed on to their sons by normal mothers. It was theorized in 1911 that this gene is located on the X chromosome. The reasoning was that every male child gets one defective gene on the X chromosome from his mother and acquires the disease, while his female siblings get two X chromosomes -- one each from both parents. Now if the maternal X chromosome is defective, even then the girls see normally because a normal, and dominant, copy of the gene is provided from the paternal X chromosome. Some other diseases, most notably sickle cell anemia, were ascribed to the sex chromosomes on similar grounds, but the rest of the genome remained an uncharted territory for geneticists for a long time afterwards. In the 1960s, techniques to hybridize human and mouse chromosomes were developed and led to the attribution of about one hundred genes to different chromosomes.

In the 1970s, a breakthrough molecular genetics tool was developed that changed everything. Called recombinant DNA technology, this process allows researchers to cut snippets of DNA from a chromosome and insert it into bacterial plasmids. Plasmids are loops of extrachromosomal DNA in bacteria that can replicate autonomously. When these tampered plasmids replicated, they made numerous copies, or clones, of themselves, along with the human snippet. As the methodology of the process was refined, the discovery and assignment of different genes to chromosomes also caught pace.

Meanwhile, in 1977, Fredrick Sanger at Cambridge and Walter Gilbert and Allan Maxam at Harvard, devised an ingenious technique to sequence -- or to know the exact base order -- of any portion of a chromosome. The technique employs restriction enzymes that work like molecular scissors and cut the DNA thread at any desired location into pieces of any size. These pieces are then ordered and separated by using gel electrophoresis. A laser reads the base order of the fragment and the information is stored on a computer. Modern sequencing methods have become increasingly automated and a latest sequencer can determine the base order at the blinding speed of about 75,000 bases per day.

Another extremely valuable tool of the trade was developed in late 1980s by American biochemist Kary Mullis who was rewarded with the Nobel Prize in 1993). Called polymerase chain reaction (PCR), the process can churn out millions of clones of a small fragment of DNA in a few hours. In fact, PCR did for genomic research what the Xerox machine did for copying.

PROJECT STATUS

On March 9 this year, the HGP reached an important milestone. 11,000 workers in 16 different labs around the globe announced the sequencing of the 2 billionth base pair of the genome. This means that two thirds of the task has already been done. At this pace, the working draft of the genome (90% of the genome at 99.9% accuracy) will become available by June this year. In December 1999, the HGP consortium published the code of chromosome 22 in Nature, the first chromosome to be completely deciphered.

When the project was inaugurated, the official finishing date was set to be 2005. But thanks to mounting pressure by several private companies -- who saw the commercial opportunities of genomic research -- the Project was forced to scurry a little and now the deadline has been set in 2003, a year that celebrates the golden jubilee of the discovery of the double helix structure of DNA. Celera Genomics' Craig Venter -- who vowed in 1998 to beat the official project by cracking the genome in 2001 -- has in particular proven to be a gadfly for the Project think tank. Celera uses a different approach, called short-gunning, than the publicly funded Project. This method relies heavily on computational powers and Celera accordingly possesses the world's most powerful supercomputer in their lab.

WHOSE GENOME ARE WE TALKING ABOUT?

Every human being out of more than six billion now alive is unique in such characteristics as height, weight, hair, complexion, intelligence, temperament, and a thousand others variables. There are six billion variations on the genomic theme so to speak. The natural question then: whose genome is the HGP decoding? Actually, the above-mentioned differences are overwhelmed by similarities between different members of the species. It has been estimated that only about 3 million bases, out of a total of 3.2 billion, are different in any two human beings. This means that there is only 0.1% genetic difference between this scribe and the movie star Leonardo diCapprio! (So where are the sprawling fan clubs?)

The labs at various centers attached with the Project collect blood samples from different people and then clone and enhance their DNA and sequence it. When completed, the genome would be a tapestry of DNA collected from thousands of individuals, but would nevertheless be a true blueprint of Homo sapiens sapiens as a species.

IMPLICATIONS OF THE PROJECT

Although being a remarkable intellectual and technological feat when finished, the HGP will not be the end of genetics as we know it. It would, on the contrary, provide a template for generations to come to work on it and understand how organisms develop, live and die. As stated earlier, from 70-90,000 still await discovery. When the sequence is complete, the next aim will be not only to locate the rest of the genes, but also to pinpoint various proteins that these genes make, the mutations that can result in disease and so on.

Following are some of the areas that will profit immensely from the project:

Basic Research

The sequenced genome will lead to answering one important, and very basic question: is the genomic order critical? What would happen, for example, if one particular gene were swapped with another gene on another chromosome? Another fundamental question that begs an explanation is what tells parts of the genome to express differently in different body cells? What drives a pancreatic cell to synthesize insulin, and not hemoglobin, when the genes of both the proteins are present in the cell?

Another striking application will be the comparison of other organisms' genomes with the human genome, and the detection any similarities and divergences. Research conducted so far suggests that the human genome is not that original at all. In actual effect, it's an amalgam of genes taken from other animals, plants and even microorganisms. The genes responsible for the replication of human DNA, for instance, have stunningly similar counterparts in bacteria. And a chimpanzee's genome is 98.5 % identical to our own!

Moreover, it has been found that the lowly fruit fly Drosophila melanogaster shares 68% of cancer genes with us; while a small worm C. elegans has analogues of half of all known human disease genes. These comparisons can also shed light on the course of evolution of life and in classification of organisms into groups.

Diagnostics

Some geneticists claim that all diseases are genetic in origin. This statement might be a little exaggerated, but the fact remains that most diseases have some genetic connotations. Currently, some 4000 disorders have been recognized that are the result of a mutation in the genome. A complete genome, with all the defective genes categorized, will help greatly in diagnosing and assessing a person's risk of contracting a disorder. This may lead to early and successful treatment of an otherwise fatal affliction even before the symptoms develop.

Pharmacogenomics

Pharmacogenomics is the hottest buzz world in the healthcare industry these days. It focuses on measuring tiny differences, called single nucleotide polymorphism (SNP, pronounced "snip") among the genomes of different people. How frequently these variations occur can be illustrated with the help of an analogy: If the genome were a 4.5 meter wide and 80 thousand kilometer long brick road, only one brick would be different every 18 km (one SNP disagreement) between the genomes of two people. If a map is made of all the SNPs of a given population and epidemiological data is collected, it would be possible to predict whether one person will benefit from a drug or develop a serious adverse reaction to it. This will prove extremely useful in optimizing pharmacotherapy and dosage regimens, and tailoring them to individual needs. One example will clear the point: About 1% of the population cannot metabolize azathioprine because they have a defective copy of the gene that codes the enzyme thiopurine methyl transferase, which is necessary for the drug's metabolism. (Azathioprine is a drug used for the treatment of leukemia and some autoimmune disorders.) When such patients are prescribed the drug, they may experience potentially myelosuppression because the drug accumulates in their bodies. A test for the detection of variants of the gene is in use at two US hospitals, the Mayo Clinic and at Saint Jude Children's Research Hospital.

And this is not just about orphan drugs. According to genomic scientists, 85% of the patient's response to drugs is due to genetics. For example, up to 50% of the population does not respond to antidepressants, 35% do not benefit from ?-blockers, while 30% are impervious to the effects of statins. Tests for these and other adverse effect-boding genetic variations will help immensely to minimize, if not completely wipe out, the incidence of iatrogenic disorders.

Drug Discovery

Today's pharmaceutical companies discover drug mostly on a blind trial-and-error method. They screen thousands of candidate compounds to see if any one has the desired pharmacological properties. But genomic research is bound to change this by making available data on disease-validated target molecules, enabling companies to produce novel chemical entities to fight the diseases.

ETHICAL, LEGAL AND SOCIAL IMPLICATIONS

Although the benefits of the HGP to the welfare of humankind cannot be overstated, one must not overlook some ethical and social ramifications of the project. Some circles fear that potential employers and insurers can use the genetic predisposition of a person to a certain disease against him. An insurance company, for instance, might refuse to insure a person who has a genetic predisposition to contract a certain disease in future.

Then comes the issue of "designer babies". If all the traits of a human being are characterized, and tests are developed to identify them in the fetus, some parents may opt for a taller, smarter, or a handsomer baby; and might abort a fetus that does not pass these criteria. This may have unpredictable consequences for the society.

There are also fears about some private biotechnology companies patenting and commercializing parts of the genome. This concern is so real that it prompted the US President Bill Clinton and the British Premier Tony Blair in March this year to issue a joint statement urging the need for a freely available database of genetic information as soon as it is acquired.

The complete genomic code has been dubbed by many as the book of life. And it would be a grand book indeed, deserving a place on the same shelf as Plato's Republic, Dante's Divine Comedy and Shakespeare's Hamlet.