The Cancer Journal - Volume 6, Number 4 (July-August 1993)
Another triumph for gene transfer....a fishy story - should we swallow it whole?
A piece of information in Nature (362, 411, 1993), signed by Robin Weiss, caught my imagination. Transgenic mice have recently been endowed with the capacity to grow without limit and without aging. This led the author to cite the famous "The Portrait of Dorian Gray", in which Oscar Wilde illustrates the legend of Faust so well.
Let us go back in history. The longevity of carp and of giant tortoises has always intrigued the curious, biologists and curious biologists, including Obispo and Maunciple. Since 1967, these two authors have succeeded in extracting a protein from the intestines of the carp, which is able to prolong the life of mice. This protein, christened longevin, is a heterodimer of a heat-labile B chain produced by Escherichia coli in the carp's digestive flora and a A chain which comes from neuroendocrine cells in the intestinal wall. The B chain has been sequenced and cloned, so that Obispo was able to produce mutations more stable at mammalian body temperature. This gene was transfected into bacteria which were then introduced into the digestive tract of mice. Here the B chain increased the longevity of the mice, but at the price of becoming covered with scales (!) and of multiple carcinoid colon tumours developing in 20% of the animals, tumours which produced large quantities of both serotonin and the A chain of longevin. This was meticulously described in Nature 11 years ago (296, 392-393, 1982).
Since, few biologists have been adding natural longevin to their diet in order to live longer. The memory of what one must do to avoid growing old: read Nature, take note of what one has read and eat raw carp intestines (especially on Fridays, it seems), has been short-lived.
Thanks to molecular biology, considerable progress has been made between 1982 and 1993. The gene tith, found in počkilothermic but not in homeothermic vertebrates, has been cloned. The gene product, tithonin, is similar to the A chain of longevin. In 1989 it was introduced into a transgenic mouse which grew to a respectable size before dying young of cardiac insufficiency.
More mice were transfected with the tith gene modified to make its product better adapted to homeotherms: the result was animals which were able to grow without stopping (?) and without becoming covered in scales. However, they did become photophobic, like Oedipus in Greek myth.
To avoid the danger of immortalized mice escaping from the laboratory into nature, the tith gene is now being combined with a lethal gene for conditional apoptosis. In this case, they are kept alive by a small amount of morphine in their drinking water. In this way, only those mice who can find a poppy field soon after escaping will be able to survive. Science has rarely come so close to the stuff of the ancestral myths, and molecular biologists have never been so close the conquering death.
Two small points may or may not be significant. Those who know Robin Weiss will confirm that he has a strong sens of (British) humour; and both the Nature articles, in 1982 and 1993, appeared in the issue dated 1st April. I am waiting patiently for the next issue of Nature to be published on the first day of April (get out your Almanach, 1999). I can afford to be patient because I am now confidently eating my raw carp entrails every Friday and before eating them I read my future in them. What is more, I pay scrupulous hommage to the goddess Mol Biol, faithfully saying my sancta simplicita molecularis.
(CNRS, BP 8, 94801 Villejuif cedex, France - e-mail: firstname.lastname@example.org)