Talking Points
Contents:
Genetic mutation underlies thrombotic thrombocytopenia pupura (4/11/01)
The possibility of immunization against Alzheimer's disease (8/7/99)
Streptococcus Streptococcus tolerant to vancomycin (10/6/99)
Responses:
Genetic mutation underlies thrombotic thrombocytopenia pupura (4/11/01)
Thrombotic thrombocytopenia purpura (TTP) is a life-threatening disorder in which there is destruction of red blood cells and blood platelets, and the formation of small blood clots in the vessels of several organs. This results in anaemia, thrombocytopenia (diminished numbers of platelets), kidney damage, and nervous system dysfunction. Modern treatments such as the infusion of freshly frozen plasma have greatly reduced mortality from TTP. Levy et al (2001) have now demonstrated the genetic fault underlying this disease, opening up the possibility of better treatment in the future. Mutations in the gene ADAMTS13 on chromosome 9 result in the lack of an enzyme which normally cleaves large protein aggregates in the blood called the von Willebrand factor (VWF). This factor mediates interactions between platelets, and between platelets and blood vessel walls, helping to maintain a balance between clotting and bleeding.
Levy, G.G., Nichols, W.G., Lian, E.C., et al (2001) Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature, 413, 488-494 (4 Oct).
(For more on this subject, see our page on TTP) - (Not done yet - in Blood Disorders)
Protein aggregates cause neurons to die (12/7/01)
Several degenerative diseases
of the nervous system such as Huntington's disease and Alzheimer's disease are
associated with abnormal accumulations of proteins within and sometimes around
neurons. There has been continuing discussion about whether these protein
aggregations are the initial cause of neurodegeneration or simply a consequence
of it. Now Perutz and Windle (2001) propose that the aggregations in
Huntington's disease are indeed responsible for neuron death. Huntington's
disease has been traced to a triplet repeat in the gene for a large protein of
unknown function. The number of repeats differs from one individual to another -
if less than 37 the person will be healthy, but if more than 40 the disease will
appear. The greater the number of repeats in affected individuals, the earlier
the emergence of the disease. The authors have used this evidence to demonstrate
that aggregation of Huntington's protein is probably the cause of neuron death
in this disease.
Perutz, M.F., and Windle, A.H. (2001) Cause of neural death in neurodegenerative
diseases attributable to expansion of glutamine repeats. Nature, 412, 143-144
(Jul 12).
Polio outbreak caused by mutated vaccine (18/1/01)
Seven cases of vaccine-induced polio have been confirmed in the Dominican republic and neighbouring Haiti. The weakened, live virus used in the oral polio vaccine had mutated and regained the ability to cause the disease. This has come at a time when the World Health Organization is in the final stages of the global eradication of the wild poliovirus. The number of cases of polio worldwide has fallen by over 99% in the 12 years that the vaccination programme has been in place. The aim is to eradicate this paralysing disease by 2005. It is unlikely that an alternative vaccine can be brought into use - the Salk inactivated polio vaccine has a number of disadvantages including high cost and the need for injection, and there is probably insufficient incentive to develop a completely new vaccine.
Neurokinin B: a cause of pre-eclampsia? (15/6/00)
Pre-eclampsia is a problem that affects 5-10% of first pregnancies and is a significant cause of illness and death for mothers and babies. The main features are raised blood pressure, protein loss in the urine, disorders of blood clotting, and oedema. The evidence points to involvement of the placenta. Page et al (2000) have demonstrated that a likely candidate for the initiation of pre-eclampsia is over-production by the placenta of a signalling molecule identical to neurokinin B. Neurokinin B is known to have hypertensive actions through its effects on blood vessels and the heart. The identification of this link between neurokinin B and pre-eclampsia may enable the development of a test to allow early detection of pre-eclampsia and treatment with neurokinin receptor antagonists.
Page, N.M., et al (2000) Excessive placental secretion of neurokinin B during the third trimester causes pre-eclampsia. Nature, 405, 797-800 (Jun 15).
Human genome (first draft) (11/5/00)
Within the next few months, two draft versions of the human genome will be completed. One is being prepared by the 16-centre international Human Genome Project, and the other by the private company Celera Genomics. The complete sequences of two chromosomes have already been published - chromosomes 21 and 22. (These are relatively small chromosomes.) There will be gaps remaining in the draft versions of the genome and it is anticipated that another 3 years will be required to achieve the definitive sequencing of the human genome.
Air entering the nose is split into two streams by the nostrils and the streams remain separated internally by the nasal septum. It is perhaps surprising that the relative quantity of air in each stream changes over time: airflow on the left may initially be greater than on the right due to greater swelling of the highly vascular tissues over the right conchae, and then the relationship is reversed within a few hours when the tissues over the left conchae swell and the right conchae reduce in size. Sobel et al (1999) now present evidence that this periodic switching provides the brain with two slightly different images of the scented world, and suggest that this might enhance olfactory acuity.
Sobel, N., Khan, R.M., Saltman, A., Sullivan, E.V., and Gabrieli, J.D.E. (1999) The world smells different to each nostril. Nature, 402, 35.
Vegetables influence bone metabolism (23/9/99)
Osteoporosis occurs most frequently in post-menopausal women. Various dietary supplements have been tried with a view to reducing the loss of bone density, for example increased calcium intake via dairy products and phytoestrogens in soy. The success has been limited. Now Mühlbauer and Li (1999) have demonstrated that several vegetables that are common in the human diet have a significant effect on bone density in the rat. If a similar effect is found in humans, then inclusion of these vegetables in the daily diet could be beneficial.
Mühlbauer, R.C., and Li, F. (1999) Effect of vegetables on bone metabolism. Nature, 401, 343-344.
The possibility of immunization against Alzheimer's disease (8/7/99)
Alzheimer's disease is a progressive dementia accompanied by the loss of neurons in the hippocampus and cortex of the brain, and the accumulation of characteristic proteins inside and outside surviving neurons. The extracellular protein is aggregated into plaques which are largely composed of amyloid-ß peptide. Nerve endings in the proximity of amyloid plaques become misshapen. Schenk et al have demonstrated in a mouse model of Alzheimer's disease that immunization with amyloid-ß can inhibit these degenerative changes. Although the approach has not yet been tested in humans, there is a possibility that immunization will provide benefits in the prevention and treatment of Alzheimer's disease.
Schenk, D. et al (1999) Immunization with amyloid-ß attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature, 400, 173-177.
Malaria parasite causes immunosuppression (3/7/99)
The malaria parasite Plasmodium falciparum needs to suppress the immune system of its human host in order to build up its numbers in the bloodstream sufficiently to guarantee transmission to other hosts by mosquitoes. Urban et al (1999) have announced this week that the plasmodia do this by interacting with dendritic cells whose job is to present foreign antigens to cells of the immune system. Infected red cells attach to the dendritic cells and inhibit them from maturing, thus reducing their ability to stimulate an immune response.
Urban, B.C., Ferguson, D.J.P., Pain, A., Willcox, N., Plebanski, M., Austyn, J.M., and Roberts, D.J. (1999) Plasmodium falciparum - infected erythrocytes modulate the maturation of dendritic cells. Nature, 400, 73-77.
Streptococcus tolerant to vancomycin (10/6/99)
Streptococcus pneumoniae is a bacterium responsible for several serious diseases, including pneumonia and meningitis. It has become resistant to most of our antibiotics, and vancomycin has become the antibiotic of last resort for treatment of disease caused by resistant strains. Now there is evidence of tolerance even to vancomycin. Tolerance means that the micro-organisms stop growing in the presence of vancomycin but remain alive, rather than being killed by it. This change in resistance has been atributed to a mutation in genes prescribing a signalling pathway within the bacterium.
Gilmore, M.S., and Hoch, J.A. (1999) A vancomycin surprise. Nature, 399, 524-527.
Helicobacter pylori has a protective role Helicobacter pylori has a protective role has a protective role Helicobacter pylori has a protective role has a protective role Helicobacter pylori has a protective role Helicobacter pylori has a protective role (2/5/99)
The bacterium Helicobacter pylori can colonise the stomach and cause gastritis and peptic ulcers. These disorders can now be treated effectively by the use of antibiotics that kill H. pylori. However, recent evidence has revealed that H. pylori can also have a protective role in people exposed to high levels of harmful organisms in their food and water. H. pylori generates antibacterial peptides that can kill other rapidly-growing organisms but not itself. Thus it is both a cause of disease and a protection against disease. In that sense it resembles sickle cell anaemia - a genetic fault that alters haemoglobin and creates disease whilst giving some protection against malaria - and cystic fibrosis, again a genetically-based disease that may in the past have given protection against endemic cholera.
Putsep, K., Branden, C.-I., Boman, H.G., and Normark, S. (1999) Antibacterial peptise from H. pylori. Nature, 398, 671-672.
An alternative to heparin (4/4/99)
Heparin is a polysaccharide widely used for the last 50 years in the prevention and treatment of cardiovascular disease. It reduces the tendency of blood to clot (coagulate) by binding with antithrombin (a protein in the blood) and enhancing its inhibitory effect on blood clotting. However, heparin has the unwanted side-effects of increasing the risk of bleeding and depressing the production of blood platelets. An alternative anticoagulant has been synthesised that has a powerful antithrombotic effect without these drawbacks, and will progress shortly to clinical trials.
Petitou, M. et al. (1999) Synthesis of thrombin-inhibiting heparin mimetics without side effects. Nature, 398, 417-422.
Working draft of human genome by Spring 2000 (19/3/99)
The Human Genome Project is an international effort to sequence the 3 billion base pairs of the DNA-carried genetic code in human cells. The project is progressing so well that the deadline to produce a working draft of the genome - 90% of the sequence - has been brought forward by 18 months to Spring of next year. The effects of this achievement will be profound, and influence not only the practice of medicine but many other aspects of every-day life too.
The National Human Genome Research Institute
Hair may provide basis for breast cancer screening (8/3/99)
X-ray diffraction studies of scalp and pubic hair have revealed that breast cancer can be reliably diagnosed by this method - the scatter-patterns from women with breast cancer show an additional diffuse ring. This may arise from differences in cell membrane structure in affected people. The testing of pubic hair eliminates inconsistencies caused by hair treatments such as perming.
James, V., Kearsley, J., Irving, T., Amemiya,Y., and Cookson, D. (1999) Using hair to screen for breast cancer. Nature, 398, 33-34.
Vancomycin synthesized (25/2/99)
Only 2 antibiotics are effective against methycillin-resistant Staphylococcus aureus (MRSA): vancomycin and teicoplanin. These polypeptides work by binding to cell wall components of growing bacteria and blocking their further development. Already, vancomycin-resistant strains of enterococci are emerging, particularly in hospitals. This is a serious situation, and efforts to find alternative antibiotics are being stepped up. An important advance has been reported by Nicolaou and colleagues - the complete synthesis of vancomycin. This will facilitate the search for modified antibiotics effective against MRSA.
Nicolaou, K.C. et al (1999) Angew. Chem. Int. Edn., 38, 240-244.
Cyclosporine and cancer (17/2/99)
Cyclosporine suppresses the immune system, and is given to transplant patients to reduce the risk of rejection. One of the worrying side-effects of long term treatment with this drug is an increased risk of cancer. This was believed to be due to cancer cells not being recognised and eliminated by the suppressed immune system. Now Hojo et al have found that cyclosporine has a direct effect on cancer cells, stimulating them to divide and migrate. This effect seems to be mediated by the signalling molecule transforming growth factor-ß. It is not clear yet whether cyclosporine induces the transformation of normal cells into cancer cells or exerts its effect on existing tumour cells only.
Hojo, M. et al (1999) Cyclosporine induces cancer progression by a cell-autonomous mechanism. Nature, 397, 530-534.
We have tended to assume that human embryos have a built-in tendency to follow the female developmental pathway, and that to become male requires specific developmental signals that begin with the expression of the testis-determining factor gene on the Y-chromosome. Now Vainio et al have demonstrated that female development is not automatic after all, and requires the activity of a local signal specified by the gene Wnt-4. This gene product influences several processes, including the development of the female genital ducts, the ovaries, and steroidogenesis more generally. In the absence of Wnt-4 control, males develop normally but females become masculinised.
Vainio, S., Heikkile, M., Kispert, A., Chin, N., and McMahon, A.P. (1999) Female development in mammals is regulated by Wnt-4 signalling. Nature, 397, 405-409.
Morphine and immunity (27/1/99)
Morphine and other opioids have been used for centuries as potent painkillers. Their effects on the nervous system and addictive nature have been closely studied, but now there is evidence that they influence the immune system too - they produce immunosuppression. Yin et al report that morphine induces lymphocytes to express a cell-surface receptor which, when activated, causes the cell to close down (apoptosis) and thus lead to a reduction in lymphocyte number. Opioids are also known to suppress the production of cytokines (signalling molecules) within the immune system and thereby inhibit the immune response. It is hoped that these findings will give a greater insight into the close relationship between the nervous system and the immune system.
Yin, D., Mufson, A., Wang, R., and Shi, Y. (1999) Fas-mediated cell death promoted by opioids. Nature, 397, 218.
At conception, 23 chromosomes from the mother come together with 23 chromosomes from the father to form the genome of the new individual. Most of the genes are therefore duplicated, with one copy of maternal origin and the other of paternal origin. Generally, only one gene of each pair will need to be expressed in a particular cell. The most marked example of this is seen in the cells of females, who receive an X-chromosome from each parent - one of the X-chromosomes is almost completely 'switched off' in each cell. Sometimes, the decision about which gene or chromosome is expressed is determined by parental origin. Paternal and maternal genes are imprinted during development of the gametes, and the imprint is maintained throughout embryonic development of the new individual. The multistage mechanism by which imprinting is achieved is now better understood following the publication this week by Birger et al of an imprinting 'box' in an imprintable gene - a short stretch of DNA that can become methylated and provide the imprint.
Birger, Y, Shemer, R., Perk, J., and Razin, A. (1999) The imprinting box of the mouse Igf2r gene. Nature, 397, 84-88.
Adult thymus remains active (21/12/98)
The thymus is very active during our childhood years, producing competent T cells for the immune system. In adult years, the thymus shrinks and its lymphoid tissue is largely replaced by fatty tissue, leading to the interpretation that function is being lost. Now Douek et al (1998) have shown that the thymus remains able to produce T cells even in later years, although at a reduced rate. Infection with HIV damages thymic function, while treatment with highly active antiretroviral therapy boosts the output of new T cells.
Douek, D.C. et al (1998) Changes in thymic function with age and during the treatment of HIV infection. Nature, 396, 690-694.
Operating on spina bifida in utero (13/12/98)
Over recent years, fetal surgery has been introduced for several conditions where the possible benefits outweigh the potential hazards of intervention. For example, fetuses with diaphragmatic hernia, hydrocephalus, and obstruction of the urinary tract have been operated upon before birth to enhance subsequent development. Eight weeks ago, a corrective operation was carried out on the neural tube defect of a 23-week fetal boy at the Philadelphia Children's Hospital. The exposed, abnormal region of the developing spinal cord was covered with soft tissues to reduce the degenerative process that would have otherwise occurred in the neural tissue before birth. In this way, it is hoped that there will be less loss of neurological function to the lower part of the baby's body and lower limbs. To date, there have been no complications following surgery.
Alcoholism and neuropeptide Y (1/12/98)
There have been several reports linking genetic factors to an increased risk of alcoholism, and Thiele et al (1998) reported this week that a particular signalling molecule distributed throughout the nervous system is involved. Neuropeptide Y is an inhibitory neuromodulator already shown to influence learning, memory, and emotional status, and mice lacking the gene for this peptide consume more alcohol whilst showing less sensitivity to its effects. Thus, there is an inverse relationship between the level of neuropeptide Y in the mouse brain and the consumption of alcohol. It is known that people with a low sensitivity to alcohol are more likely to become alcoholic, and it will be interesting to see whether neuropeptide Y has a role in humans too.
Thiele, T.E., Marsh, D.J., Ste. Marie, L., Bernstein, I.L., and Palmiter, R.D. (1998) Ethanol consumption and resistance are inversely related to neuropeptide Y levels. Nature, 396, 366-369.
Embryonic stem cells (15/11/98)
A few days ago American scientists reported that it is possible to clone embryonic cells with a view to producing human tissues and organs. This technique has the potential to produce effective cell replacement treatments for diseases such as Parkinson’s disease and diabetes, but of course raises difficult ethical questions. Here in the UK research of this kind is currently banned, but the Human Fertilization and Embryology Authority may now apply to the UK government to change the legislation controlling embryological research. The justification would be that the transplanted cells would benefit the affected individual without there being a risk of the effects being passed on to the next generation.
High doses of aspirin are used in the treatment of chronic inflammatory diseases such as rheumatoid arthritis, but until this week it was not clear how aspirin moderates the immune response. As noted in one of our earlier answers, it is already known that aspirin inhibits the production of prostaglandins and thus reduces the pain and fever associated with infection or trauma, but now there is evidence that high doses of aspirin also inhibit the production of transcription factors that initiate the immune response.
O'Neill, EA (1998) A new target for aspirin. Nature, 396, 15-17.
Endocrine disruptors (31/10/98)
There is widespread concern about endocrine disruptors - human-made chemicals that are suspected of adversely affecting fertility in our own and other species. Some pesticides, industrial chemicals and drugs seem to mimic sex hormones, and they may be linked for example with the falling sperm counts reported in several countries. It was announced in the US this week that the Environmental Protection Agency is planning to screen 15,000 chemicals to see which if any have a disruptive effect, and in Japan researchers at four universities will begin a similar search.