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Researchers identify a possible new target for treatment of malaria
SCIENCE AND MEDICINE
Cloned mice have a shorter lifespan than “normal” mice
T
he controversy about somatic cloning is further fuelled this week by a report that suggests that the lifespan of cloned mice is significantly shorter than that of mice with the same genotype born after normal mating. Atsuo Ogura (Riken Bioresource Center, Tsukuba, Japan) and colleagues cloned 12 male mice from immature Sertoli cells and examined their weight gain and serum biochemistry over their lifespan. Each parameter was also measured in two control groups of mice of the same strain: those produced by normal mating, and those derived from spermatid injection. The weight gain of cloned mice and controls showed no differences for the first year of life. However, at 3 and 14 months, cloned mice had higher serum concentrations of lactate dehydrogenase and ammonia than controls. The cloned mice started to die 311 days after birth; 10 of the 12 mice died by day 800. By contrast, one control mouse born after natural mating and two mice derived from
spermatid injection died within this timespan. Six of the cloned mice were examined after death; all were found to have severe pneumonia, and four of them had extensive necrosis of the liver (Nat Genet 2002; online publication; DOI: 10.1038/ng41). “Impairment of the immune system of cloned mice seems a strong possibility”, says Ogura. In a separate experiment, the researchers found that cloned mice showed reduced antibody production as early as 4–5 months after birth. Phagocytic activity was also lower than in controls. The cause of this immune dysfunction is not known, but Tony Perry (Center for Developmental Biology, Kobe, Japan) suggests two possibilities. “The underlying mechanism may be a fault in the reprogramming of the donor nucleus following transfer. One minute this is issuing instructions to maintain a somatic cell, and the next is required to switch to begin the embryonic developmental
programme. The consequences of this reprogramming can be subtle, specific, and delayed”, he says. In addition, Perry believes that physical trauma experienced by cells during the cloning process might also be a contributory factor. “This study reports that the ‘controls’ generated by spermatid injection were also susceptible to greater premature death and tumorigenicity than ‘normal’ controls; this is consistent with a phenotypic influence by micromanipulation”, he adds. The physiological problems associated with cloning are only now being identified, and the mechanisms and causes need further investigation. However, Ogura stresses that “the possible negative long-term effects that we have identified, as well as the high incidence of spontaneous abortion and abnormal birth of cloned animals, give cause for concern about attempts to clone humans for reproductive purposes”. Kathryn Senior
Researchers identify a possible new target for treatment of malaria promising drug interference is blockage of the choline transporter that provides the intracellular parasite with choline, a precursor required for synthesis of this major parasite phospholipid.”
Rights were not granted to include this image in electronic media. Please refer to the printed journal. Plasmodium infection of erythrocytes
Vial and colleagues tested the effects of G25, a choline analogue that binds competitively to the choline carrier, thus inhibiting choline transport into infected erythrocytes. They found that intramuscular injection of G25 completely cured monkeys that were infected with either P falciparum or P cynomolgi malaria (n=23 in total). G25 was effective at doses far below those used for current antimalarial drugs, and there was no recrudescence of
THE LANCET • Vol 359 • February 16, 2002 • www.thelancet.com
Science Photo Library
idespread resistance of Plasmodium falciparum malaria to common antimalarial drugs is a major problem, especially in subSaharan Africa, highlighting the need for alternatives to existing treatments that are affordable for poorer nations. Now, an international team of researchers report that they have identified a potential new class of drugs for the treatment of malaria. “Development of these new antimalarial drugs for oral administration as both preventive and curative malaria treatment in humans is now a realistic objective”, comments lead researcher Henri Vial (Université Montpellier II and CNRS, France). The investigators now aim to develop an oral formulation that can be used as a cheap alternative to chloroquine. During asexual multiplication of the malaria parasite within erythrocytes, considerable amounts of membrane are synthesised, for which phospholipid biosynthesis is essential. “The biosynthesis of phosphatidylcholine in Plasmodium is of particular interest since it is the most abundant lipid, accounting for half of the total phospholipid in parasite membranes”, explains Vial. “The most
W
disease. Oral administration of G25 also appeared to be fully effective (Science 2002; 295: 1311–14). “Vial’s group is to be congratulated for their elegant identification and exploitation of a new target in Plasmodia”, comments Peter Winstanley (University of Liverpool, UK). “They have methodically developed and tested a range of inhibitors of phosphatidylcholine synthesis, and have identified some ‘front runners’. These drugs are extremely potent, apparently absorbed from the oral route, and apparently well tolerated by non-human primates.” The researchers are now concentrating their efforts on developing new compounds that have improved oral absorption. “We consider that oral administration is essential for dispensaries in endemic countries that often do not have adequate facilities to safely give drug injections, and that it is also indispensable for prophylactic or curative treatments for travellers”, says Vial. “We would like to be able to choose one candidate for preclinical studies within the next 2 years at a maximum.” Helen Frankish
587
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Cloned mice have a shorter lifespan than “normal” mice
T
he controversy about somatic cloning is further fuelled this week by a report that suggests that the lifespan of cloned mice is significantly shorter than that of mice with the same genotype born after normal mating. Atsuo Ogura (Riken Bioresource Center, Tsukuba, Japan) and colleagues cloned 12 male mice from immature Sertoli cells and examined their weight gain and serum biochemistry over their lifespan. Each parameter was also measured in two control groups of mice of the same strain: those produced by normal mating, and those derived from spermatid injection. The weight gain of cloned mice and controls showed no differences for the first year of life. However, at 3 and 14 months, cloned mice had higher serum concentrations of lactate dehydrogenase and ammonia than controls. The cloned mice started to die 311 days after birth; 10 of the 12 mice died by day 800. By contrast, one control mouse born after natural mating and two mice derived from
spermatid injection died within this timespan. Six of the cloned mice were examined after death; all were found to have severe pneumonia, and four of them had extensive necrosis of the liver (Nat Genet 2002; online publication; DOI: 10.1038/ng41). “Impairment of the immune system of cloned mice seems a strong possibility”, says Ogura. In a separate experiment, the researchers found that cloned mice showed reduced antibody production as early as 4–5 months after birth. Phagocytic activity was also lower than in controls. The cause of this immune dysfunction is not known, but Tony Perry (Center for Developmental Biology, Kobe, Japan) suggests two possibilities. “The underlying mechanism may be a fault in the reprogramming of the donor nucleus following transfer. One minute this is issuing instructions to maintain a somatic cell, and the next is required to switch to begin the embryonic developmental
programme. The consequences of this reprogramming can be subtle, specific, and delayed”, he says. In addition, Perry believes that physical trauma experienced by cells during the cloning process might also be a contributory factor. “This study reports that the ‘controls’ generated by spermatid injection were also susceptible to greater premature death and tumorigenicity than ‘normal’ controls; this is consistent with a phenotypic influence by micromanipulation”, he adds. The physiological problems associated with cloning are only now being identified, and the mechanisms and causes need further investigation. However, Ogura stresses that “the possible negative long-term effects that we have identified, as well as the high incidence of spontaneous abortion and abnormal birth of cloned animals, give cause for concern about attempts to clone humans for reproductive purposes”. Kathryn Senior
Researchers identify a possible new target for treatment of malaria promising drug interference is blockage of the choline transporter that provides the intracellular parasite with choline, a precursor required for synthesis of this major parasite phospholipid.”
Rights were not granted to include this image in electronic media. Please refer to the printed journal. Plasmodium infection of erythrocytes
Vial and colleagues tested the effects of G25, a choline analogue that binds competitively to the choline carrier, thus inhibiting choline transport into infected erythrocytes. They found that intramuscular injection of G25 completely cured monkeys that were infected with either P falciparum or P cynomolgi malaria (n=23 in total). G25 was effective at doses far below those used for current antimalarial drugs, and there was no recrudescence of
THE LANCET • Vol 359 • February 16, 2002 • www.thelancet.com
Science Photo Library
idespread resistance of Plasmodium falciparum malaria to common antimalarial drugs is a major problem, especially in subSaharan Africa, highlighting the need for alternatives to existing treatments that are affordable for poorer nations. Now, an international team of researchers report that they have identified a potential new class of drugs for the treatment of malaria. “Development of these new antimalarial drugs for oral administration as both preventive and curative malaria treatment in humans is now a realistic objective”, comments lead researcher Henri Vial (Université Montpellier II and CNRS, France). The investigators now aim to develop an oral formulation that can be used as a cheap alternative to chloroquine. During asexual multiplication of the malaria parasite within erythrocytes, considerable amounts of membrane are synthesised, for which phospholipid biosynthesis is essential. “The biosynthesis of phosphatidylcholine in Plasmodium is of particular interest since it is the most abundant lipid, accounting for half of the total phospholipid in parasite membranes”, explains Vial. “The most
W
disease. Oral administration of G25 also appeared to be fully effective (Science 2002; 295: 1311–14). “Vial’s group is to be congratulated for their elegant identification and exploitation of a new target in Plasmodia”, comments Peter Winstanley (University of Liverpool, UK). “They have methodically developed and tested a range of inhibitors of phosphatidylcholine synthesis, and have identified some ‘front runners’. These drugs are extremely potent, apparently absorbed from the oral route, and apparently well tolerated by non-human primates.” The researchers are now concentrating their efforts on developing new compounds that have improved oral absorption. “We consider that oral administration is essential for dispensaries in endemic countries that often do not have adequate facilities to safely give drug injections, and that it is also indispensable for prophylactic or curative treatments for travellers”, says Vial. “We would like to be able to choose one candidate for preclinical studies within the next 2 years at a maximum.” Helen Frankish
587
For personal use. Only reproduce with permission from The Lancet Publishing Group.