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Enhancing Human Life with Genetic Science
by Tan Lay Leng

n the not-so-distant future, humans may enjoy a relatively disease-free existence in the 21st century. We may be able to analyse our children's genes and predict whether they will be predisposed to heart disease or asthma for example - and take steps early on to protect them. We may also be able to assess our response to drugs and find ways to circumvent adverse reactions.

Furthermore, we may be able to obtain personal health profiles, identifying those illnesses most likely to attack each of us. Then we can fortify ourselves with the proper diet, lifestyle or medication to minimise their severity or avoid them.

Genetic science has begun to revolutionise the prevention, detection and treatment of illnesses. In a few more years, thanks to the Human Genome Project (HGP), scientists will be able to determine the genetic blueprint of a human being. The Human Genome Project will transform the way medicine is practised. With a genetic roadmap of human life, medicine in the future will not simply be a matter of diagnosing symptoms and providing cures. It will start at the most basic, molecular level. Long before a faulty gene wreaks havoc, medical science will be ready and waiting.

Scientists are already able to identify and map at least 8,000 genes in the human genome, including those linked to sickle-cell anaemia, Alzheimer's disease and a host of other degenerative diseases. In addition, scientists are looking at using genes as therapy to improve or even restore a person's health.

Singapore's Genomics Push

This disease-free utopia, however, will take a lot of persistence and commitment on the part of the medical community to become a reality. Research and pharmaceutical companies have long been investing in this area, but their activities have been recently spurred by the exciting knowledge revealed by the HGP. The importance of health and a better life in an increasingly sophisticated society means the demand for the best treatments or cures will grow with corresponding rewards to the providers.

As a developed nation, Singapore too realises the significance of this trend. It has earmarked Life Sciences as a new pillar of its economy and set up a fund of more than S$2 billion since last June to drive the strategy.

One of the initiatives is the establishment of the S$62 million Singapore Genomics Program (SGP) to spearhead its efforts. The SGP will use the latest in genomics, proteomics and bioinformatics technology to identify novel genes and molecular targets in endemic diseases in Asia. The information will be employed for diagnostic and therapeutic applications.

As a highly urbanised society, Singapore shares many disease characteristics found in the West, but there are subtle differences. For instance, the average age of breast cancer patients in the country is 40 years, 20 years younger than in the West. The incidence of diseases such as liver cancer, systemic lupus erythematosus and myopia is much higher compared to the West.

Furthermore, differences in susceptibility to diseases is observed among the races. For example, nasopharyngeal cancer strikes mainly at the Chinese population. SGP will be looking at these diseases which are prevalent in Singapore. A preliminary study conducted recently in Singapore shows that there is indeed significant difference among ethnic groups in the gene causing hypertension.

The NUS Genetics of Hypertension (NUSIGHT) Study is jointly carried out by the National University of Singapore's Department of Medicine, and the Laboratory for Molecular Genetics, Defence Medical Research Institute in Singapore. The work is done in conjunction with the Department of Clinical Pharmacology at St Bartholomew's and Royal London School of Medicine and Dentistry in London.

The researchers collected DNA samples from more than 120 Chinese families in Singapore with one or more hypertensive persons, making a total of some 300 individual samples. The preliminary results of genotyping using specific genetic markers are compared with one marker on Chromosome 17 previously validated by Professor Mark Caulfield at the St Bartholomew's and Royal London School of Medicine and Dentistry, London. The Singapore data suggest that the marker validated in a British (Caucasian) hypertensive population and in a St Vincent island (West African origin) hypertensive population is not associated with hypertension in Singapore's Chinese population.

Preliminary evidence shows that a different genetic site might be associated with hypertension in Singapore's local Chinese. However, Professor Vernon Oh, Senior Consultant Physician with the Department of Medicine at NUS, cautions that more validation is required from a larger sample. He adds that even when causative genes for hypertension are identified, it will be some years before any 'gene therapy' can be proposed which is likely to prevent or treat hypertension. This is because several genes are likely to be involved, and there are considerable technical difficulties in modifying the working of genes in a reliable way.

Treating Diseases with Genes

Although very few gene-based treatments have so far made it into clinical practice, gene therapy holds the most promise of any branch of genomics. The science of gene therapy rests on a simple premise: since genes direct the assembly of every cell in the body, it should be possible to permanently treat a number of devastating diseases by patching in bits of DNA to repair defective and missing genes. Nowadays, scientists try to slip therapeutic genes into useful strands of DNA and splice them into vehicles or vectors that can penetrate cells.

In addition, gene therapy methods act directly on harmful genes byinterfering with the gene's production of proteins or by blocking the action of the proteins. To date, numerous research and experiments have been conducted on gene therapy through the use of decoy promoters, antisense molecules and synthetic antibodies. Herceptin is an example of a synthetic antibody that has seen some success in the treatment of breast cancer.

Associate Professor Kong Hwai Loong, from the NUS Faculty of Medicine, is one Singapore-based doctor particularly interested in gene therapy research. In 1996, he collaborated with Dr Ronald Crystal at the Cornell Medical Center in New York to develop a way of transferring genes into our body to fight cancer. The genes are equipped with the special capability of shutting off the blood supply to cancer cells. Unlike other methods, this method does not directly act on the cancer cells per se, but rather on the blood supply, which plays a very important role in the growth of these cells.

Compared with the conventional way of treating cancer with drugs, Kong and his colleagues try to deliver genes, instead of drugs. This is because with genes, the gene expression or effects can be prolonged. With this method, a one- or two-time gene transfer is delivered to shut down the blood supply, allowing the gene to do its work like a slow-release capsule.

Back here in Singapore, Kong is developing the method further, specifically for liver cancer which is characterised by a rich blood supply. In addition, he is doing research on tumours that have spread to the abdominal cavity such as ovarian cancer, stomach cancer and colon cancer.

Yet another Singapore researcher is working on anti-sense DNA sequence for gene therapy. Dr Coral Lai Poh San and her team members from the NUS Department of Paediatrics are collaborating with the International Center for Medical Research at Japan's Kobe University on treating the debilitating effects of Duchenne muscular dystrophy (DMD) which affects 1 in 3,500 male children. They have identified a gene mutation in the X chromosome which can be artificially created to alleviate the crippling symptoms. Both teams will be starting trials on patients soon.

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