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Take two genes and call me

by Peter Lavelle

By the end of this century, today's medical treatments may seem as primitive as the purgatives and leeches of the Middle Ages. Gene technology is set to revolutionise the way we treat disease.

Published 24/06/2004

Take two genes and call meiStockphoto

In the last 200 years, medicine has come a long way. Anaesthetics and antiseptics took the pain and much of the risk out of surgery. In industrialised countries, antibiotics and vaccines wiped out most of the killer epidemics. But by the end of this century, some believe there will have been another revolution – making today's treatments seem as primitive as the purgatives and leeches of the Middle Ages. Scientists believe that by 2100, therapies that have gene technology at their heart will have completely changed the way we treat disease.

(If you're not sure what a gene is, let alone gene technology, you might like to view our Back to basics box for a crash course before you read on.)

Ten years ago, treating hereditary diseases with genes from a test tube was pie in the sky stuff, says the University of Technology Sydney's professor of biochemistry, Dr Ann Simpson. But gene therapy has made significant advances in the last decade and currently includes efforts to combat common conditions like cancer, heart disease and diabetes.

However, most of the early work – and the early successes – were in treating diseases caused by mistakes (or mutations) in single genes, Dr Simpson says. There are about 4000 of these. They are uncommon conditions like cystic fibrosis, haemophilia and muscular dystrophy; occasionally the result of random mutations in an individual soon after conception, but more commonly passed down through generations.

While they can sometimes be treated, they can't be cured. Haemophilia for instance is caused by the lack of a crucial chemical involved in blood clotting. Without it, a person risks bleeding to death from a minor injury. Treatment involves replacing the missing clotting factor. But it's costly and must continue over the life of the sufferer.

Researchers in the early 1990s realised that a much better approach would be to correct the defective gene or replace it with a fully-functioning version that would restore the cell's functions. It sounded simple enough in theory. But in practice, it's turned out to be anything but.

Just getting the replacement gene into the body is a challenge for a start. You can't simply swallow it or inject it, because the body's immune system recognises it as foreign and destroys it, says gene therapy researcher Dr Panos Ioannou, from Melbourne's Murdoch Children's Research Institute. You also have to make sure it reaches the cells you want to target.

If it's liver disease you're trying to treat, you have to get the gene into the liver, for example. You have to make sure it penetrates the boundary of the cell, known as the cell wall. And you have to make sure it's actually expressing; in other words, doing its job of coding for proteins in sufficient amounts that will correct the defect. In most cases, the gene needs to keep expressing proteins for the life of the patient. And you need to make sure it isn't interfering with the function of other genes that might be essential to good health.


Back to basics

In almost every cell in the human body are around 25,000 or so individual genes. These are instructions or recipes for chemicals called proteins. These proteins govern how we are made, as well as many aspects of our appearance, behaviour, and our health.

These instructions or genes are encoded in a chemical called DNA, which stands for deoxyribonucleic acid.

DNA is made up of four building blocks: chemicals called adenine, thymine, cytosine and guanine, often abbreviated to the letters A, T, C and G.

These building blocks are arranged in pairs, and strung together in a long strands. In humans, there are 3.2 billion pairs in total.

The orders of the chemical pairs or letters affects the information encoded in the DNA.

Scientists have determined the basic order of all the chemical building blocks or letters in the entire sequence of human DNA. But there are subtle differences between one person and another, which can have a strong influence on health and susceptibility to disease. The details of these links are still being unraveled.

Gene therapy is a field of medical research which uses gene technology - ways of manipulating genes - to prevent disease or enhance health.

'If we play our cards right this should be the century where we unravel how life works and apply that in a benevolent way to the prevention and cure of many diseases that currently vex and frustrate us and I think that's going to be a wonderful adventure.'

- Dr Francis Collins, Director of the National Human Genome Research Institute, speaking at an ABC forum at the XIX International Congress of Genetics in Melbourne, 2003.


The bubble boys

Of all the barriers to gene therapy, the most difficult initial problem is delivering the gene into the cell. A breakthrough came in the late 1990s and involved a group of children with a rare genetic deficiency called severe combined immunodeficiency. It left their bodies unable to make vital immune cells known as T cells, responsible for destroying invading micro-organisms.

T cells are made in the bone marrow, the soft inner part of the bone, from unspecialised cells known as stem cells. Having this gene defect meant the children could not make normal T cells. Infections that would be mild in other people with normal immune systems, would be deadly. The usual treatment for the condition is a bone marrow transplant. But that depends on a suitable donor – such as a sibling – being available. Otherwise the child has to live his or her life isolated from the outside world in a plastic enclosure known as a 'bubble'.

Scientists extracted bone marrow from the sick children and used an ingenious piece of engineering to get a replacement gene into the stem cells in the marrow. A functioning gene was inserted into a common type of virus called an adenovirus, which had been altered so that the virus no longer caused disease. The adenovirus has evolved a special knack of being able to enter cells without being detected by the immune system. This made it an ideal 'carrier'; bypassing the body's immune system, and transporting the gene safely into the cell, where it could be processed by cell machinery to produce the missing protein.

Reinserted back into the bone marrow, the modified stem cells produced normal T cells; the children had normal immune responses and were able to lead normal lives outside their 'bubbles'. Excitement spread throughout the world of research and interest in biotechnology soared.


Obstacles to success

But for each success, there were many more failures. While immune deficiency diseases are unusually well-suited to the gene replacement technique, most single gene diseases aren't, says Dr Panos Ioannou, who heads Murdoch's Cell and Gene Therapy research group. 'You can't treat conditions that involve solid tissue this way,' he says.

The problem is getting the gene into the tissue. With bone marrow, it's technically easier to insert genes. But it is harder to get replacement genes into the cells of mature tissue on organs like the heart. And that's what you need to do to treat degenerative diseases of muscle, nerves or the brain.

And even in cases where solid tissue wasn't the problem, other difficulties arose. Two of the boys who'd undergone the gene therapy treatment for severe combined immunodeficiency developed leukaemia. The replacement gene that worked so well at restoring their immune system, apparently interfered with other genes known as tumour-suppressing genes, whose function was to prevent the growth of certain cancers like leukaemia.

There were other sorts of unforeseen consequences too. In 2000, an 18-year-old boy died of multiple organ failure after he was injected with an adenovirus carrying a gene to treat his rare liver disorder. As well as infecting the liver cells, the virus attacked other vital body organs, causing a fatal inflammatory response.

These safety concerns, along with the limited success of the gene replacement technique in general, had the effect of putting a break on research on single gene disorders. But it didn't stop other gene therapy efforts from going ahead.


A cure for cancer?

All diseases – not just those rare ones arising from defects in single genes – have a genetic basis of some sort or another. The way we react to infections and toxins in the environment, for instance, depends on our genetic makeup. And many people have variants of normal genes than make them more susceptible to commonly-acquired conditions like cancers, heart disease, strokes, and diabetes.

Only in the presence of separate interacting factors – such as other genes or certain environmental triggers – does the disease actually develop. These diseases run in families because susceptibility to these external factors is passed down the generations.

Many of these diseases are the big killers in our society, so much of the research going on is directed at them, says Professor Ann Simpson. Currently there are around 150 clinical trials of gene therapies being conducted worldwide, involving about 3000 patients. The bulk of these are focusing on acquired diseases involving multiple genes; conditions such as cancer – which alone accounts for around 70 per cent of projects – HIV, heart disease, and diabetes, she says.

Just which genes are involved in these common diseases and how they interact with the environment and other genes isn't well understood. 'So you can't just identify a faulty gene, and replace it with a functioning one,' says the Murdoch Institute's Dr Panos Ioannou. Instead researchers are trying different approaches; improving expression of 'under performing' genes, or introducing genes to influence other cell systems that would compensate for, or overcome, the effects of the multiple gene defects.

Dr Ioannou believes it's here that the greatest chance of success lies. And because multi-gene disease is so much more common than single gene disease, it's also where we have most to gain.


Avenues of attack

There's a wide range of different gene therapy approaches being trialed, depending on the disease. Some involve genes for growth factors, substances that encourage the growth of new tissue. This might be new blood vessels in areas of heart muscle damaged by poor blood supply, new nerve calls in degenerative nerve disease such as multiple sclerosis, or new muscle cells in muscle-wasting diseases like amyotrophic lateral sclerosis.

Many of these trials, though promising, are being carried out in animals, and have yet to be shown to be effective in humans. However, some human trials do raise hope; growth factors injected into the brains of people with Alzheimer's disease have been shown to slow the progress of dementia.

Other treatments are designed to boost the immune system. Cancer cells can be manipulated to alter chemicals on their surface known as 'markers'. This has the effect of making them more recognisable to the immune system, which can more readily destroy them.

A cancer's spread can also be limited by the insertion of so-called 'tumour-suppressor' genes, which stop cells becoming cancerous. In many cancers – for example head, neck and pancreatic cancers – tumour suppressors are missing, and by introducing replacements, growth of the cancer can be stopped.

Some gene treatments might also work by enhancing existing treatments. Cancer cells can be injected with genes that make them more sensitive to chemotherapy or radiation. Or the cells that are precursors to blood cells can have a gene added that would make the blood cells more resistant to the side-effects of anti-cancer drugs.

And screening for genetic disease will get more and more sophisticated. Professor Mary Hendrix is head of the department of anatomy and cell biology at the University of Iowa and a member of the United States' National Advisory Council for Human Genome Research. She says that within the next decade every child will be given a 'genetic passport' shortly after birth.

'These genetic passports will provide vital information regarding the child's predisposition to hundreds of illnesses with a genetic link, such as heart disease, obesity, osteoporosis and some forms of cancer,' she says. 'Imagine for a moment the possibility of identifying genes in newborns responsible for cardiac disease, or diabetes, or arthritis, or specific cancers, and then managing and/or preventing the onset of these diseases.'


Prophets and profits

Clearly, the advantages gene therapies can bring are massive – and not just in terms of relieving suffering and prolonging life. The economic benefits could also be significant. While the treatments are likely to be expensive initially, their cost is ultimately expected to fall below that of conventional therapies. Given that in the United States, traditional treatments for cancers alone amount to over $100 billion annually, that could be a very substantial saving. Then there's the indirect savings from populations that are healthier and live longer.

An Access Economics report, Exceptional Returns: The value of investing in health R&D in Australia, reveals that between 1960 and 1999, the female lifespan increased from 73.9 to 81.8 years and the male from 67.9 to 76.2. These longevity gains were worth $5.4 trillion, according to the report, which was commissioned by the Australian Society for Medical Research and released in October 2003. Every dollar spent on health research and development returns at least $5 in national economic benefit, the report says.

For corporations too, huge profits might be made. The private sector plays a crucial role in commercialising gene technology treatments developed by academic and government-funded research institutions. In the late 1990s, after the initial successes of gene technology, biotech companies scrambled for patents, and investors poured funds into the sector. Biotech companies raised billions of dollars in public floats. But by 2000, the sector had crashed. Investors sold down, fed up with regulatory interference, abandonment of trials because of safety concerns, and the dearth of treatments coming onto the market.

As Professor Bob Williamson, Chairman of the Murdoch Children's Research Institute puts it bluntly: 'The hype around gene therapy was totally unrealistic, driven by dreams of clinical miracles and financial reward, neither of which have eventuated.'


The Holy Grail

So far, gene therapies are all in the experimental stage. There is not a single one on the market; instead only promising results exist from trials in various stages. Yet the effort continues, driven by the Holy Grail of medicine: treatments that cure underlying conditions rather than merely their symptoms. To patients – and their doctors – a cure is of course infinitely preferable to a lifetime of treatment.

There are signs the biotech industry is reviving. There are now 613 biotech companies listed on stock exchanges worldwide and another 3,749 unlisted firms, according to business consulting firm Ernst & Young. Last year, between them, these companies generated US$41.4 billion in revenue – up 15 per cent on the year before.

Australia is the Asia-Pacific region's leading biotech country, home to 38 listed companies worth more than US$5 billion. However, Australia trails behind Canada, the United States, the United Kingdom, Switzerland, France and Japan for public sector funding of research.

'In the long run, the use of genes will be a major contribution to therapy,' says Professor Williamson, 'but the road will be a rather longer one than we thought. The reality will be a slow and steady progress over the next ten to 20 years.'