A new genetic paradigm

Print edition : July 08, 2000

Backed by technology and computing power, genetics for the millennium now comes replete with terms and terminologies dictated by a new paradigm.

R. RAMACHANDRAN

THE announcement on June 26 that the "draft" sequence of the complete human genome has now been completed, which has been hailed as one of the most significant scientific landmarks equivalent to man landing on the moon or the splitting of the atom or eve n the invention of the wheel, as one report put it, is greatly hyped and needs to be viewed in the proper perspective.

A scanning probe microscopic image of human chromosomes.-REUTERS

True, to read all the alphabets of the genetic blueprint - about 3.2 billion characters - that codes human life, to have a fair idea of the assembly order in which they occur in the human deoxyribonucleic acid (DNA), and to be in a position to read the v arious genetic sentences that make up the "book of life" is no mean achievement. But to call it a major scientific enterprise is a misnomer. It is only a technological achievement in the sense that what scientific endeavour, in the true spirit of discove ry, would have achieved perhaps well into the next century has been turned on its head to do the same by brute force.

The approach of classical genetics would have been to understand the variety of functions of the human system in molecular terms - proteins and their structures - and then look for appropriate genes and the sequences of basic chemical characters on them that code for these functionalities one by one and in time perhaps complete the entire human genome. Technology and computing power, which are overtaking the speed with which science was advancing, turned modern pursuit of genetics into a new sequence -> structure -> function paradigm. Genetics for the new millennium now comes replete with new terms and terminologies dictated by this new paradigm.

It was as if inventors of new technologies, the rapid sequencing machines which could sequence up to 1,000 basic units from each end of a DNA fragment a day, and modern genetic techniques were getting impatient with the slow unravelling of the complete g enetic code in the usual discovery-led path of science. That the following were among the chief goals of the Human Genome Project (HGP) reflects this inverted paradigm:

President Bill Clinton, flanked by (left) J. Craig Venter, head of Celera Genomics, and Francis Collins, Director of the Human Genome Project of the National Institutes of Health, United States as he announced on June 26 that two teams had completed a rough draft of the human genetic code.-REUTERS

* identify all the approximately 100,000 genes in the human DNA;

* determine the sequences of the three billion chemical bases that make up the human DNA; and

* store this information in databases.

Once an international programme (though dominated by the United States), which brought together hundreds of workers to do the routine of merely recording the sequences on the fragments of cloned DNA pieces in laboratories of as many as 18 countries and s ystematically recording them, was put in place and once high-speed automated machines and robots got into the act, it was only a matter of time that this massive - and impressive nevertheless - enterprise would achieve the goals.

It is because of the largely routine nature of the project, given the number of machines involved and the sequences that could be read in a day, milestones could be set with fair certainty. The approach in this predominantly public-funded programme was t o go step by step, identify specific laboratories to carry out the complete sequencing of specific chromosomes which in turn farmed out the effort to different laboratories by distributing (overlapping) fragments, based on their capacities and available funding, for them to sequence using sequencing machines. Using appropriate available genomic maps (at various resolutions) that have been generated over the years, and identifying matching ends of fragments by their overlapping nucleotide bases, the sequ enced DNA stretches are assembled to give the entire chromosomes.

Mike Dexter (right), Director of the Wellcome Trust, and Dr. Michael Morgan, Chief Executive of the Wellcome Trust Genome Campus, at a press conference in London on June 26.-CHRISTINE NESBITT/A

The original target year for the completion of the project was 2003 with the draft sequence being ready by the latter half of 2001. In December 1999, the first-ever complete sequencing of one chromsome (chromosome 22), complete with annotations required for the precise location of 33.4 million base pairs (Mbp) of the 56 Mbp, was finished. It was stated that there were 11 gaps to be fixed by further analysis. Chromosome 22 is one of the shortest among the 24 chromosomes in the human genetic make-up, the largest being chromsome 1 with 263 Mbp. The fact that draft sequences of chromosomes 5, 16 and 19 had also been announced earlier in the year suggested that sequencing of other chromosomes was also well on its way to completion. Also, given the advances in techniques of sequencing, some scientists felt that the draft of the complete genome might appear in the first half of 2001 itself rather than later. This was further reinforced by the swift announcement of the complete sequence of chromosome 21 - the shortest, with 50 Mbp.

However, as against chromosome 22, the uncertainty here was greater and the annotations were far from complete. It was becoming clear that this was a fallout of the announcement made by Craig Venter in April 2000, who had only in September 1999 formed th e company Celera Genomics in partnership with Perkin Elmer Biosystems Inc., the makers of the high-speed sequencing machines, that Celera had completed the sequencing as well as the re-assembly of the fragments and would come out with a draft sequence of the complete human genome in six weeks. What is now being hailed as the result of partnership and joint efforts of private and public-funded genomic research, is actually a facade marking the culmination of an ongoing confrontation between Celera (and o ther private companies engaged in genomic sequencing) and the public-funded programme in the research laboratories of the U.S., the United Kingdom and other countries of Europe.

While it is true that the HGP had nearly three-fourths of the genome sequence already in the public domain by April, and Celera, notwithstanding its claims, had not allowed public access to any of its data, it is the fear that Celera might end up patenti ng the primary sequences of the genome as well as random short gene sequences which the policy and ethical guidelines of the Human Genome Organisation (HUGO), the world body formed in 1988, to coordinate the international efforts in human genome research , explicitly prohibits.

Unlike the systematic chromsome-by-chromsome approach of the HGP, Venter is the originator of the so-called shot-gun approach where the DNA of all the chromsomes are randomly chopped up and the fragments are sequenced randomly. The matching and assembly of the sequences to give the full stretch of the DNA is done with the aid of the computing power of supercomputers. The fact that this technique gives 99 per cent accuracy in the final assembled sequence was demonstrated by Venter in the genomic analysis of smaller organisms like bacterial genomes and of the fruitfly (Drosophila). The fact that Venter might be able to win the private-public race in sequencing of the genome, and hence lay claim to the primary genome sequence, was becoming real.

Dr. John Sulston, Director of the Sanger Centre, near Cambridge, United Kingdom, which was involved in the Human Genome Project.-REUTERS

Last year Celera had announced that it had filed preliminary patents on 6,500 whole or partial human genes, but will take only a few of them through the full patent process. Venter had said at that time that Celera would hold to a promise made at hearing s before the U.S. Congress that it would seek to patent no more than 100 to 300 genes. It was apparent that the announcement on June 26 made jointly by the public-funded programme and Celera, complete with political statements by U.S. President Bill Clin ton and British Prime Minister Tony Blair, was following some kind of compromise worked out between Celera and the international HGP.

This is apparent from the remarks of John Sulston, director of the publicly funded Sanger Centre in the U.K., who said: "I hate to fight but I am glad that I fought (Celera)." The factor that seems to have brought around Venter is that Celera had used al l the data that have been put out in the public domain by the HGP all these years for assembling its data and produce its rough draft of the genome. As a result of this compromise, Venter has agreed to put all his data too in the public domain. Although whether he does so or not remains to be seen, he has promised that he would put the basic genomic data, complete with annotations, for public access by the end of the year. Otherwise he runs the risk of being ostracised by the scientific community and of not being even nominated for the Nobel Prize, which is certainly on the cards for this enormous technical feat of the complete decoding of the human genome.

In the normal course of the HGP, given that the achievement is the result of an international effort, with the genomic mapping techniques and sequencing techniques that enabled the sequencing the entire genome having come from various laboratories in dif ferent countries, one would have expected the announcement of the completion of sequencing the human genome, its assembly and annotation, to come from the HUGO, the proper scientific forum cordinating the effort, and not through the political heads of tw o countries. By doing so, the U.S. and the U.K. have clearly used this to upstage other countries in their claim to what has been achieved. What is at stake is not merely who all get the Nobel Prize - though its rules will have to be changed to award the prize to so many workers from so many countries - but control over this basic data of the human genome. HUGO's statement on benefit-sharing made in April 2000 (see box) clearly states that the basic genomic data is the common heritage of humanity.

The completion of the human genome sequencing, in this sense, is clearly devoid of that thrill of discovery and uncertainty that was part of the splitting of the atom or even the landing on the moon, the latter too being largely technology-driven. But th ere is an essential difference, as proponents of this brute force approach would perhaps argue. Unlike the landing on the moon or the splitting of the atom, the mind-boggling amount of data, which will now be in the public domain, have obvious relevance to the betterment of human life in terms of faster association of genetic disorders as well as the predisposition of certain diseases to specific coding errors in the DNA and suitable therapies to counter them.

However, while huge databases of genetic information will be created, none-too-clear guidelines exist as of now as to how to analyse and use these for the most efficient and beneficial use for mankind with unethical and blatantly commercial use of data b eing highly probable.

While HUGO's guidelines on patenting explicitly forbid patenting of full gene sequences and short sequences such as Expressed Sequenced Tags (ESTs) or complimentary DNAs (cDNAs), and subscribes to the European Biotechnology Directive of 1998, the award o f patent to a private company Incyte Pharmaceuticals by the U.S. Patents and Trade Marks Office for Human Kinase Homologues in October 1998, gave rise to concern. This was the first patent given to an EST. HUGO considers ESTs and other such random short gene sequences from isolated points in the DNA to be research tools and is therefore opposed to their patenting, trends in the U.S. seem to be going against it especially in the wake of statements made by Venter and other private enterprises.

A computer illustration of the double-helix structure of the DNA.-REUTERS

Most significantly, even within the context of HUGO policy guidelines, while innovative products based on gene sequences do, of course, become patentable, even the mere association of a functionality with a gene sequence, like a facet of a disease or a c ertain manifestation of a disease, is patentable. Knowledgeable sources believe that the final agreement on genomic data is likely to be of this nature that while primary data may not be patentable - even this could be violated because after all this is only a guideline - discoveries of associations of diseases, disorders and human traits with gene sequences will be patentable.

The most serious danger to deriving benefits for humanity in general lies here. This is likely to lead to arbitrary and even spurious and overbroad claims on functionalities of gene sequences thwarting medical progress in the real sense. Already there is growing difference of opinion between European scientists and U.S. scientists on this issue as was evident in the last Cold Spring Harbor meeting. It is time for member-countries (which number over 50 today and include many developing countries, includi ng India) to strengthen this forum and ensure that undue commercial explotiation of basic genetic data of peoples of the world does not take place. While the first war between public and private interests may seem to have been won, the battle of genes i s likely to dominate in the years to come.

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