Athought-provoking study, recently published in Nature Reviews Genetics,1

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1 Australia Athought-provoking study, recently published in Nature Reviews Genetics,1 considered the consequences of an increased exposure to micronutrients. A tricky question, given the widespread, sometimes even mandatory, practice of food fortification. The results suggest that the widespread practice of fortifying food with folic acid could be slowly changing the genetic make-up of the population, perhaps even predisposing future generations to be more vulnerable to fatal diseases. Folic acid is a type of B vitamin that is vital for many metabolic processes, and it is added by law to flour and grain products in some countries. This ensures that pregnant women, who are often unaware of their pregnancy early on, eat enough folic acid to reduce the risk of their babies developing defects in the brain and spine. But the longterm safety implications of boosting folic acid are unknown. There are fears that high doses might accelerate the progression of certain cancers, for example. Vitamin Fortification Could Play a Role in Genetic Selection 1 Folic Acid Vitamin and Panacea or Genetic Time Bomb? Nature Reviews Genetics 6 : , Lucock and Yates, who conducted the study, examined a small collection of studies showing that the babies of women on diets rich in folic acid are more likely to carry a particular form of a gene involved in metabolizing the vitamin, called 677T MTHFR, as compared to the children of women who did not receive adequate folic acid. Such studies have found that fetuses carrying this gene variant are more likely to survive to birth if their mothers are getting an adequate or abundant intake of folic acid. And because widespread folic-acid fortification and vitamin supplements ensure that more and more mothers do indeed get high levels of the nutrient, the number of children carrying this variant could be climbing. This change of genetics could have a negative effect on health over time, Lucock suggests. This is because several studies have shown that this same form of the gene, 677T MTHFR, may increase the risk of various conditions in adults, including heart disease, certain forms of cancer and complications of pregnancy. These harmful effects of the gene are more common when people s diets are low in folic acid. It s not clear why this might be, but as long as people s diets remain high in folic acid, Lucock proposes, this would compensate for any adverse impacts of 677T MTHFR. However, this widespread fortification could effectively create a future population that is artificially dependent on copious quantities of the vitamin and one that would be more vulnerable to certain fatal diseases if that supply vanished. At present, Lucock believes that the health benefits of folic-acid fortification for pregnant women outweigh the potential future risk. But until the potential health risks of fortification are clearer, he suggests that governments could consider lowering their recommendation on how much folic acid should be added to food. A caveat: this is only an early study. Other researchers say that there is not yet enough evidence to say whether or not this genetic selection is taking place. APBN Vol. 9 No

2 Singapore USING THE ZEBRAFISH TO STUDY HUMAN DISEASES The female hormone, oestrogen, affects many genes and is related to diseases such as breast cancer and osteoporosis. Oestrogen levels are replenished in menopausal women using hormone replacement therapy (HRT), but the use of this method is highly controversial as it results in many unwanted side effects and also raises the risk of stroke. Thus, there is a need to better understand human development before searching for more effective alternative treatments. Dr Zhiyuan Gong from the Department of Biological Science, National University of Singapore (NUS) is a zebrafish expert. His group wants to find out how individual genes react to oestrogen: whether it causes them to work harder by instructing the cells to produce more of a certain protein, work less than normal, or has no effect. 180 APBN Vol. 9 No

3 The male zebrafish is used as they produce less of the hormone naturally. First, the scientists extract genetic material from fish which have been swimming in water containing oestrogen. This genetic material is then placed on a bandaid-sized gene chip, each of which is capable of analyzing chemical reactions in more than 16,000 genes at a time. The genes which have been tagged with red fluorescent dye attach to their corresponding genes on the chip. Those which respond to oestrogen will produce more copies of themselves, which is measured in the amount of red dye appearing on the chip. The team s work on oestrogen s effects on one particular gene (there are an estimated 40,000 in the zebrafish genome) are due to be published soon in the scientific journal Gene. By studying the effects of mutations in the zebrafish, scientists are able to gain a further understanding of human physiology and disease, such as heart function, hearing, blood formation, vision, cartilage and bone formation, nervous system development and even cancers. For example, mutations in the development of blood cells in the zebrafish genome closely resemble human diseases such as anemia and thalassaemia. Associate Professor Vladimir Korzh of the Singapore Institute of Molecular and Cell Biology (IMCB) said he chose the zebrafish in 1990 when he was researching the function of specific genes in simple vertebrates. Rapid progress in the field shows that the fish is a useful tool in understanding human development, as well as how many hereditary and infectious diseases develop in people. Why Zebrafish? It has a short life cycle, thus easily kept and bred in the laboratory. Adult fishes are about 4 cm long and the female can lay 200 eggs per week. They reach maturity in two to three months. Their embryos are transparent, thus scientists can study them easily and see which are developing, which genes have been activated and where this is taking place in the fish. Its genome is half the size of mice and humans, thus easy genetic amenability. It shares many of the same genes as humans, so work on it can shed light on how the same genes work in humans. It plays an important role in understanding other genomes and gene functions. 182 APBN Vol. 9 No

4 Singapore New Bone Implants That Resemble Natural Bone Researchers at the Singapore Institute of Bioengineering and Nanotechnology (IBN) have successfully developed an ideal bone scaffold for reconstructive surgery. Using animal bone and a US-patented tissue processing technique, the IBN team, led by Dr Pei-Lin Mao, prepared an implantable anorganic scaffold that has the original chemical and physical properties of natural bone. Tests have shown that it maintains the natural threedimensional conformation and chemical components with non-homoegeneous distribution of trace/essential elements and can be shaped easily for specific treatments. Currently, orthopedic patients receive bone grafts from several sources. One method is to obtain bone from a different part of the patients body (autograft). Although autografts are highly recommended for patients with serious bone defects, they require additional surgery and may result in further infection at the donor site. Bone Implants Other procedures involve the harvesting of bone from another person (allograft) or animal (xenograft). Allografts are restricted by the limited donor bone supply and patients run the risk of viral infection. The challenge with using acquired human or animal bone also lies with the bone graft preparation process, where the bone needs to be cleaned and purified before implantation. These bone tissues may lose their original physical and chemical properties during this preparation process, and patients still run the risk of contracting transmitted diseases with the processed bone. Most of the immune rejection is from the proteins within the bone tissue, as well as other components like cell debris. To remove these elements, stringent solvents and extremely high temperature must be applied. Those solvents that are currently available are highly toxic in nature, and are not easily removed through rinsing because of the high porosity of bone tissue. In addition, the high temperature will lead to a change in the original chemical components of the bone as well as its conformational structure. Hence, the processing of solvent-treated bone tissue can be a complex and expensive exercise. Nevertheless, the use of animal bone presents several practical advantages, such as its low cost and wide availability. Hence, to address the current problems associated with animal bone implants, Dr Mao and her team have designed a APBN Vol. 9 No

5 bioprocessed tissue preparation that eliminates the use of toxic chemicals and enzymes. The technique involves the use of natural treatments and a mild solvent on organic porcine (pig) bone. A repeated boiling process successfully disrupts the extracellular matrix (ECM) and cells without changing the physical properties of the bone scaffold. The ECM and bone marrow cells can be easily removed by further ultrasound treatment, leaving the scaffold that has almost the same properties as natural human bone. The resulting bioprocessed anorganic porcine bone (APB) retains its original architecture and components, and is hence, biocompatible and can be implanted safely without the risk of viral infection or immunological response. It is highly osteoconductive, serving as a scaffold on which bone cells can attach and grow. It is also highly osteoinductive, stimulating immature bone cells to grow and mature, thus forming healthy bone tissue. Most importantly, IBNs bone bioprocessing method is a simple procedure and can be performed at a very low cost. The bioprocessed bone can be stored under airtight conditions before implantation. Bone scaffolds of different sizes may either be seeded with the patients own cells or directly implanted into the patients body. In the near term, our technology is available immediately for use in in vitro cell culture for tissue engineering. Most significantly, the bioprocessed bone represents the natural bone scaffold and it will provide a model to elucidate the natural mechanism of bone remodeling in vitro, said Dr Mao. In the long-term, our bone material has the potential to replace all existing bone scaffold materials, as our scaffold maintains the original architecture and components that are most suitable for bone repair. 184 APBN Vol. 9 No