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Haemoglobin C protection against malaria
SCIENCE AND MEDICINE
Haemoglobin C protection against malaria haemoglobin S cells under deoxygenated conditions.” Haemoglobin S is common in most parts of sub-Saharan Africa. However, haemoglobin C, which like the S variant
Rights were not granted to include this image in electronic media. Please refer to the printed journal.
Science Photo Library
new study indicates that the risk of both severe and non-severe Plasmodium falciparum malaria is reduced in HbCC (haemoglobin CC) homozygotes by 93% compared with HbAA individuals. “We found no HbCC homozygotes with non-severe malaria and only one with severe malaria”, explains researcher David Modiano (University of Rome “La Sapienza”, Italy). “The parasite load in this patient was very low, which agrees with previous in-vitro observations that the parasite does not grow well in HbCC erythrocytes.” Knowing more about how innate resistance strategies of this type arise should help in the development of therapeutic interventions, suggests Ronald Nagel (Albert Einstein College of Medicine, Bronx, NY, USA). The protective effect of the sicklecell trait (haemoglobin S) against malaria is well established and mechanisms have been proposed to explain how protection is achieved. “There is strong evidence that the parasite induces enhanced sickling so that infected erythrocytes are removed from the circulation by the spleen”, says Nagel. “Another suggestion is that the parasite cannot prosper in
A
Plasmodium falciparum protozoan
involves a mutation at aminoacid six of the haemoglobin  subunit, is found only in central West Africa in areas of low frequency of haemoglobin S genes. Whether haemoglobin C, a benign haemoglobinopathy compared with haemoglobin S, protects against malaria in these regions is unclear. In this latest study, researchers examined 3513 healthy people and 835 patients with malaria in Burkina Faso. Haemoglobin AA, AC, and CC genotype frequencies were as expected in healthy people, but only one HbCC
patient had clinical malaria rather than the 13·8 expected (Nature 2001; 414: 305–08). “Protection is conferred mainly by the homozygous state”, says Modiano, “and we believe that this explains why the haemoglobin C mutation is concentrated in West Africa—dispersion of the mutation under the selective pressure of malaria will be more difficult for haemoglobin C than for haemoglobin S which is protective in the heterozygote state”. “The study of haemoglobinopathies in protection against malaria is important”, comments Thomas Wellems (National Institutes of Health, Bethesda, MD, USA) who last year reported that haemoglobin C is associated with protection from severe malaria in the Dogon of Mali. However, unlike Modiano, Wellems saw no protection against uncomplicated malaria in HbCC individuals. Wellems believes that these conflicting results may indicate that different haemoglobinopathies give more or less protection against malaria depending on the genetic background, environmental conditions, or both in which the mutation acts. Jane Bradbury
Protein chemistry could allow better diabetes control
S
low and gradual insulin delivery may become possible using chemically-modified insulin that is inactive until cleaved by a catalytic antibody, according to Richard Lerner (Scripps Institute, La Jolla, CA, USA), senior author of a study published this week. Good control of blood-glucose concentrations in people with diabetes helps to prevent many of the secondary complications of the disease. Lerner emphasises that there is still much work to be done but says that the study highlights the possibilities of combining organic and protein chemistry. “Theoretically, it should be possible to introduce chemical modifications to any therapeutic protein that will alter its half-life, distribution, and biological activity to elicit a therapeutic advantage”, he predicts. Dorothy Worrall (University of California at San Diego, La Jolla, CA, USA), Lerner, and colleagues have developed an aldolderived organoinsulin prohormone (insulinD) that shows reduced receptor binding in vivo and in
1702
vitro compared with native insulin. The affinity of insulinD for the insulin receptor was only 10% of that of insulin in binding studies in intact cells. In adipocytes, the ability of insulinD to stimulate glucose transport was reduced by 96%, and in conscious rats, the capacity of insulinD to stimulate glucose transport was reduced by 55%. Incubation of insulinD with a catalytic aldolase antibody (38C2) resulted in cleavage of the aldolterminated modifications, restoring the chemical structure of native insulin. Introduction of the antibody to cells treated with insulinD restored the hormone’s receptor binding and glucose transport activities. InsulinD in combination with the 38C2 antibody was also able to control blood glucose in animals (Proc Natl Acad Sci 2001; 98: 13514–18). Circulating serum concentrations of functional antibody 38C2 are sustained for a significant amount of time in mice (about 12 days) and the antibody has been recently modified for use in people.
“This should open the door for clinical testing”, says Lerner, who envisages the development of a system in which insulinD is given by daily injection, with the 38C2 antibody delivered separately using a slow-release system, such as liposomes. Slow release of antibody would enable gradual conversion of insulinD to active insulin, he adds. If developed and tested successfully, James Lenhard (Chief, Section of Endocrinology, Christiana Care Health Systems, Wilmington, DE, USA) can see this technique being useful in several ways. “It could provide a basal insulin replacement for people with diabetes who prefer the convenience of less than daily dosing; it could protect people from developing ketoacidosis, especially ketosis-prone individuals that have difficulty with compliance; and it could provide a long-acting basal insulin for people whose major physiological problem is a relative but not absolute insulin deficiency”, he comments. Kathryn Senior
THE LANCET • Vol 358 • November 17, 2001
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Haemoglobin C protection against malaria haemoglobin S cells under deoxygenated conditions.” Haemoglobin S is common in most parts of sub-Saharan Africa. However, haemoglobin C, which like the S variant
Rights were not granted to include this image in electronic media. Please refer to the printed journal.
Science Photo Library
new study indicates that the risk of both severe and non-severe Plasmodium falciparum malaria is reduced in HbCC (haemoglobin CC) homozygotes by 93% compared with HbAA individuals. “We found no HbCC homozygotes with non-severe malaria and only one with severe malaria”, explains researcher David Modiano (University of Rome “La Sapienza”, Italy). “The parasite load in this patient was very low, which agrees with previous in-vitro observations that the parasite does not grow well in HbCC erythrocytes.” Knowing more about how innate resistance strategies of this type arise should help in the development of therapeutic interventions, suggests Ronald Nagel (Albert Einstein College of Medicine, Bronx, NY, USA). The protective effect of the sicklecell trait (haemoglobin S) against malaria is well established and mechanisms have been proposed to explain how protection is achieved. “There is strong evidence that the parasite induces enhanced sickling so that infected erythrocytes are removed from the circulation by the spleen”, says Nagel. “Another suggestion is that the parasite cannot prosper in
A
Plasmodium falciparum protozoan
involves a mutation at aminoacid six of the haemoglobin  subunit, is found only in central West Africa in areas of low frequency of haemoglobin S genes. Whether haemoglobin C, a benign haemoglobinopathy compared with haemoglobin S, protects against malaria in these regions is unclear. In this latest study, researchers examined 3513 healthy people and 835 patients with malaria in Burkina Faso. Haemoglobin AA, AC, and CC genotype frequencies were as expected in healthy people, but only one HbCC
patient had clinical malaria rather than the 13·8 expected (Nature 2001; 414: 305–08). “Protection is conferred mainly by the homozygous state”, says Modiano, “and we believe that this explains why the haemoglobin C mutation is concentrated in West Africa—dispersion of the mutation under the selective pressure of malaria will be more difficult for haemoglobin C than for haemoglobin S which is protective in the heterozygote state”. “The study of haemoglobinopathies in protection against malaria is important”, comments Thomas Wellems (National Institutes of Health, Bethesda, MD, USA) who last year reported that haemoglobin C is associated with protection from severe malaria in the Dogon of Mali. However, unlike Modiano, Wellems saw no protection against uncomplicated malaria in HbCC individuals. Wellems believes that these conflicting results may indicate that different haemoglobinopathies give more or less protection against malaria depending on the genetic background, environmental conditions, or both in which the mutation acts. Jane Bradbury
Protein chemistry could allow better diabetes control
S
low and gradual insulin delivery may become possible using chemically-modified insulin that is inactive until cleaved by a catalytic antibody, according to Richard Lerner (Scripps Institute, La Jolla, CA, USA), senior author of a study published this week. Good control of blood-glucose concentrations in people with diabetes helps to prevent many of the secondary complications of the disease. Lerner emphasises that there is still much work to be done but says that the study highlights the possibilities of combining organic and protein chemistry. “Theoretically, it should be possible to introduce chemical modifications to any therapeutic protein that will alter its half-life, distribution, and biological activity to elicit a therapeutic advantage”, he predicts. Dorothy Worrall (University of California at San Diego, La Jolla, CA, USA), Lerner, and colleagues have developed an aldolderived organoinsulin prohormone (insulinD) that shows reduced receptor binding in vivo and in
1702
vitro compared with native insulin. The affinity of insulinD for the insulin receptor was only 10% of that of insulin in binding studies in intact cells. In adipocytes, the ability of insulinD to stimulate glucose transport was reduced by 96%, and in conscious rats, the capacity of insulinD to stimulate glucose transport was reduced by 55%. Incubation of insulinD with a catalytic aldolase antibody (38C2) resulted in cleavage of the aldolterminated modifications, restoring the chemical structure of native insulin. Introduction of the antibody to cells treated with insulinD restored the hormone’s receptor binding and glucose transport activities. InsulinD in combination with the 38C2 antibody was also able to control blood glucose in animals (Proc Natl Acad Sci 2001; 98: 13514–18). Circulating serum concentrations of functional antibody 38C2 are sustained for a significant amount of time in mice (about 12 days) and the antibody has been recently modified for use in people.
“This should open the door for clinical testing”, says Lerner, who envisages the development of a system in which insulinD is given by daily injection, with the 38C2 antibody delivered separately using a slow-release system, such as liposomes. Slow release of antibody would enable gradual conversion of insulinD to active insulin, he adds. If developed and tested successfully, James Lenhard (Chief, Section of Endocrinology, Christiana Care Health Systems, Wilmington, DE, USA) can see this technique being useful in several ways. “It could provide a basal insulin replacement for people with diabetes who prefer the convenience of less than daily dosing; it could protect people from developing ketoacidosis, especially ketosis-prone individuals that have difficulty with compliance; and it could provide a long-acting basal insulin for people whose major physiological problem is a relative but not absolute insulin deficiency”, he comments. Kathryn Senior
THE LANCET • Vol 358 • November 17, 2001
For personal use. Only reproduce with permission from The Lancet Publishing Group.