December 07, 1998

Exploiting Apoptosis - the University of Texas GRIM Patent

GRIM Patent (US #5,846,768 - December 8, 1998)

Problems resulting from the continued widespread use of pesticides has prompted some biologists to pursue other means of controlling insects. While there have been some success stories in biological control, these have not been numerous, and spraying with toxic chemicals continues to be the norm. The Texas patent attempts to address this problem by incorporating a toxic component in the genome of fertile insects.

To accomplish this, the patent has exploited one of the regulatory components of apoptosis, or programmed cell death, an essential process in multicellular animals. Responding to appropriate exterior or interior signals, the cell initiates a sequence of reactions that result in its suicide. Some examples where this is important in mammals include : (i) the massive and continuous turnover of cells in the immune system; (ii) the elimination of excess nerve cells during development of the nervous system; and (iii) the death of cells which have suffered genetic damage and hence are in danger of becoming cancerous. Clearly such a process must be kept under tight control, and recent research has revealed a number of proteins which act either to stimulate or inhibit the action of the caspases, the enzymes that cause programmed cell death.

GRIM, the subject of the Texas patent, is a one such regulatory component, whose gene has been isolated from the fruit fly Dropsophila melanogaster. When overexpressed in experimental flies, GRIM dramatically increases the probability of apoptosis. As most proteins of the apoptosis pathway are found in all multicellular animals, the Texas workers plan to apply standard molecular biology protocols in using their sequence to find its corresponding component in other species. It is probable, for instance, that similar proteins will exist in mammals as well, where they could help scientists understand basic mechanisms regulating apoptosis.

More immediately, however, the inventors have created chimeric DNA sequences, employing inducible promoters to control the expression of GRIM, and then, applying standard techniques, have produced genetically transformed fruit flies in which GRIM synthesis can be turned on in response to the signal which induces promoter activity. As an example, they have used a promoter which is activated by warming to 39oC. As expected, increasing the temperature leads to death of the transformed flies, as a result of widespread cell suicide. The inventors say various types of inducible promoters, particularly those responding to chemicals, could also be used to activate the death response. In principle, such activating chemicals could even be products produced by plants on which the insects feed. Alternatively, promoters could be used which respond to chemical sprays.

The technology is young, and we may expect that its use will become ever more widespread (for an enthusiastic and quasi-triumphalist account, see Building the Better Bug", by D.A. O¼Brochta and P.W. Anderson, Scientific American, December, 1998) . Past successes in biological control, such as the elimination of the screwworm in the southern United States and Mexico, have relied on swamping local populations with males that have been rendered sterile by irradiation. By definition, such treatments are non-propagating, and depend on the existence of relatively isolated populations of the pests, to minimize the possibility of re-entry from surrounding untreated areas.

The newer transgenic approaches, in contrast, carry with them the possibility of widespread genetic change as the transformed insects interbreed with existing populations. For many cases, such as eliminating the capacity of a given insect to act as a carrier of some pathogenic organism, dissemination of the character would seem to bear little danger, whereas for a trait as basic as apoptosis considerably more caution would seem to be in order. In particular, it will be necessary to investigate the various mechanisms of gene transfer between species (such as through infectious viruses with wide host ranges) to assess the appropriateness of a given approach.

On balance, this application of biotechnology at least reflects a desire to deal with very real problems inherent in our current agricultural practices and could result in a reduction of pesticide use to respond to very real health risks are common. Instead of questioning the basis of injunctions to wash fruit and vegetables before eating, for instance, we treat these as simple common sense."

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