Fluid genome - a paradigm shift

Debashis Banerji & Mihir Shah

THE SEQUENCING of the human genome was completed in February this year. This was a truly historic event. Even more so because its findings were quite different from those anticipated by the large body of scientists working on the project. Indeed, it appears to have propelled nothing less than a Kuhnian scientific revolution, amounting to a decisive shift in the way we look at life and its constituent elements.

The Human Genome Project (HGP) finally overthrows genetic determinism, the theory that there are simple one-to-one relationships between genes and characteristics of human beings. This has been the presumption underlying the use of recombinant- DNA technology by genetic engineers over the last 20 years. They hunt for genes that cause problems and try to insert new, more desirable genes to engineer ``better'' organisms. This entire enterprise has been brought into question by the HGP which supports a more complex and nuanced understanding of the way genes work, that was all along being advocated by molecular biologists opposed to genetic engineering. Announcing the findings of the HGP, Mr. Craig Venter, President Celera Corporation and one of the two most important scientists in the effort to map the human genome, put it very bluntly: ``In everyday language the talk is of a gene for this and a gene for that. We are now finding that that is rarely so. The number of genes that work in that way can almost be counted on your fingers. The notion that one gene equals one disease, or that one gene produces one key protein, is flying out of the window''.

Genetic engineering was based on a number of assumptions, now decisively overthrown by the HGP. It was assumed that each gene codes for a single protein molecule, adding a unique trait to the behaviour of the organism (genes govern events in a cell by creating different proteins). In a closed, one-way, linear causal pathway, proteins are encoded by DNA and, therefore, DNA may be said to encode function. Each gene is an independent unit of information. The environment acts as a trigger to activate pre- set programmes in DNA. It was also assumed that genes are stable, being passed on unchanged to the next generation.

In fact, for relatively simple diseases, such as muscular dystrophy, the one gene-one disease model appears to work very well. Unfortunately, however, this is true for only two per cent of all known diseases. In all other cases, including cancer, heart disease and manic depression (the most common targets of the genetic engineers), causation is found to be much more complex. Many genes interacting with each other appear to play a role. Also, an array of signals, including nutrient supply, hormones and electrical signals from other cells, which form the cellular environment, critically influence the course of these diseases. What is more, all of these reflect the external environment of the organism as a whole. Since each human being has a unique genetic background, mutations in specific genes that produce disease in one human body may not do so in another. Also, since many genes appear to be involved in most diseases, the effect of each specific gene is small. Thus, more importance comes to be attached to factors such as the initial conditions surrounding the development history of the individual.

The new fluid or dynamic genome view confirms what was known but ignored by genocentric biology - that no gene works in isolation. After all, genetic interaction has been part of graduate genetics for over three decades now. The HGP also confirms what has been known for years - that DNA sequences within one gene may be used in coding many proteins. There is also no more doubt, if ever there was any, that the control pathway of gene expression is not closed and linear, but dynamic and circular. Changes in the cellular environment are sensed or measured by regulatory networks of proteins that function inside each cell. These networks interpret such signals so that the cell can make an appropriate response to these changes. Thus, protein networks feed back information from the outside world to the DNA and change patterns of gene expression in a context-dependent manner.

The crucial thing to note here is that these dynamic networks have rules not specified by DNA. And this is an information management system we are only now beginning to follow. Research has started to shift in this direction. But it is clear that we simply do not know enough about the response of living cells over time to their manipulation by genetic engineering. We must also remember that while molecular biology has made great advances in describing the ``structural'' genes which affect properties of bodily parts, knowledge about the genes that regulate the activity of all the structural genes is still incomplete. All told we are still unable to ascribe any function to as much as 95 per cent of all DNA. If we really want to understand and predict the effect of the insertion of a foreign gene, we must surely take this 95 per cent into account.

This collapse of genetic determinism suggests that genetic engineering may not only be unpredictable or a failure, it may also be dangerous. The fallacy of the assumption that each gene just codes for one specific protein has time and again been exposed by unanticipated metabolic changes following single gene transfers. These changes have resulted in the appearance of very sick and monstrous transgenic animals as also unexpected toxins and allergens in transgenic plants. The lower survival capacity of transgenic plants in environments different from those where the plants were originally developed has undermined belief in unidirectional control of gene expression. This may be the reason why transgenic maize developed in the U.S. failed completely when planted in the Philippines, or why the tomato FlavrSavr developed in California did not grow well in Florida, and why Monsanto's Bt-cotton crop did not work properly in Texas because it was hotter, or in Australia because it was colder than where it was developed. The belief that genomes are stable and unchanging has led to an underestimation of the rapidity with which insects develop resistance against built-in crop pesticides. A recent study reveals how about 70 per cent of insects had become resistant to the Bt-toxin produced by transgenic plants. An additional problem is that genomes normally do not accept intrusions by foreign genes. This ``species barrier'' is one of the reasons why most gene insertion attempts fail. It also contributes to the destabilisation of genes that have been successfully inserted. Because of this it has been difficult to create genetically stable transgenic organisms.

In 1989, 37 people died and thousands were permanently disabled in the U.S. after they consumed a genetically engineered nutritional supplement. Such a dangerous, unpredictable technology needs careful regulation. But the experience in this regard has not been a happy one either. Shocking facts were revealed in a lawsuit filed by a coalition of public interest groups, scientists and religious leaders led by the Alliance for Biointegrity against the U.S. Food and Drug Administration (FDA) in 1998. The FDA was forced to make public over 44,000 pages of its files. These showed that the FDA had over-ruled many warnings by its own scientists against declaring genetically engineered foods safe. It is clear that corporate interests in biotechnology based on the old genetics have investments of billions of dollars in the pipeline. They have engaged in an unprecedented propaganda blitz, playing on the health aspirations of people everywhere. They are unlikely to allow state regulation unless powerful coalitions of consumers and farmers compel the same. If pressure of these groups grows, as in Europe, the companies will inevitably zero in on Third World markets. This is where much greater public awareness and vigilance is necessary.

As Mr. Richard Strohman, Professor Emeritus of Molecular and Cell Biology at the University of California, Berkeley, says: ``We are still in the dark ages about how organisms regulate their genomes to produce adults... while the scientific inquiry must go on, the inevitable technological applications, whether in medical centres or in corn fields, must stop - until science assures us that we may proceed while doing no harm.''

(The writers, a biologist and a social scientist respectively, teach at the Baba Amte Centre for People's Empowerment, Madhya Pradesh.)

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