Hopes alive with early genetic testing

By SIMON COLLINS, science reporter

The time is just a few years in the future. If you are at school now, it might be about the time you and your partner decide to have children.

Soon after you have conceived, your doctor takes a tiny sample of fluid from around the developing foetus, it is scanned and the information fed into a computer.

In a few minutes, the computer has the results. Perhaps your baby has a slight genetic mutation that will give her a higher chance of getting breast cancer 30 or 40 years later, or an above-average predisposition to high cholesterol.

If you are unlucky, she may have a few extra repeats of genetic elements that will make her unable to break down some of the fats in her food, depriving her of essential nutrients and killing her within a few days unless she is fed regularly with a special formula.

But even then, you would be much luckier than your parents could ever dream of, because the genetic test gives you the information you need to give her that special diet.

If she's liable to get breast cancer, she can get more frequent tests than usual. If she's predisposed to high cholesterol, she can take cholesterol-reducing statin drugs from an early age.

In short, the genetic profile allows you and your doctor to plan specific healthcare based on your child's individual needs. It makes the "one-size-fits-all" medicine of your parents' era look as crude as medieval blood-letting.

AROUND the developed world, that is the scenario for a radically new kind of health care that technology is making possible.

In New Zealand, progress is patchy. A world-leading team at Auckland's Green Lane Hospital which has developed genetic tests for rare and fatal heart disorders may have to give up in the next few months unless it gets the money it needs to carry on.

But private investors are pouring money into new genetic tests for cancer. In Dunedin's gleaming, glass-walled Centre for Innovation, a white, fridge-sized computer already spits out printouts of the human genome taken from cancer tumours.

Like every other cell in our bodies, tumour cells contain all the usual 30,000 genes that define our species. But in the tumour cells, something in a few of those genes has got slightly scrambled, making the cells grow uncontrollably.

Pacific Edge Biotechnology, a joint venture between Otago University and outside investors, uses the computer printouts to search for genetic mutations in the tumours which generate specific proteins that would show up in the blood.

Within the next two years, it hopes to find blood tests for stomach, bladder, colorectal and endometrial (uterine) cancers which could be sold to a big medical company and marketed worldwide, avoiding the need to put painful probes down the throat or up the rectum or urinary tract.

It also wants to find mutations which make some tumours highly aggressive, so that doctors can decide whether to use powerful drugs which kill the cancer cells but also make many patients sick.

"Half of the patients who receive chemotherapy get little benefit from it," says the company's research director, Dr Parry Guilford. The trick will be to find genetic markers for those tumours that do respond to drugs, and to use them only in those cases.

And this is just the start. As the genetic tests are refined, it will soon be possible to tell which tumours will respond to which drugs.

"In the past a drug would be tried on the whole population and if it succeeded in only three out of 100 patients, it would be canned," Guilford says.

"But if we know who those three people are, suddenly that drug is away again.

"Within five years we will have the ability to personalise drugs for many cancers."

Already the new technology is working for one Bay of Plenty family where people have died from a rare kind of stomach cancer for the past five generations.

At the Tamapahore Marae, high above new subdivisions at Papamoa just east of Mt Maunganui's Baypark stadium, family members used to live in fear.

"Knowing that our families were dying early, in the prime of their lives around age 24 to 40, we were always frightened that when we got to that age that was going to happen to us," says Jewel Ratema.

In 1994, the whanau decided to do something about it. They traced the lines of people who had died of stomach cancer, then sought help through Tauranga gastroenterologist Robin Scoular. Family member Maybelle McLeod contacted Otago University, which sent Dr Guilford to meet the whanau. "We gave him the job," McLeod says.

The family gave blood samples for what was expected to be a five-year project to find the genetic mutation that was causing the cancer. Just 16 months later, Guilford's team found it. Since then, all members of the family have been able to get their blood tested to see whether they have the mutation.

Early this year, 15-year-old Tauranga Boys' College student B.J. (Hone) Fraser became one of the youngest people to have the check-up. He had the cancer. Fewer than three years after his father John had had his stomach removed to stop his cancer spreading, B.J. followed suit.

"It was harder for me to go through that - finding out he had it - than it was for myself," John Fraser says.

B.J. led the haka group in his father's rugby club, Rangataua. Only a few weeks after his surgery in July, he insisted on leading the haka again. Two and a half months later, he still gets "little pains", but is working at Burger King.

John, a fertiliser worker, is back as the hooker in Rangataua's president's grade rugby team. Father and son have to eat small and often, cutting up their food as much as possible and avoiding sweet things such as icecream. John's weight dropped from 110kg to 75kg after the operation because at first he "just didn't feel hungry". Now he feels hungry "all the time" - but his body also tells him when to stop eating.

"It never lets you eat too much," he says. "I have done it once or twice, and it's very uncomfortable."

On the other side of the planet, at a science festival run in Manchester by the British Association for the Advancement of Science, Harley St cancer doctor Karol Sikora says that 10 years from now there will be genetic tests that will tell us our chances of getting all types of cancer. We will then be able to change our lifestyle to beat it - changing our diet, for example, to beat cancers of the digestive tracts.

"By 2013, cancer will be a chronic controllable illness like HIV. Patients will still die, but hopefully after a short period of illness at the end of a normal lifespan," Sikora says.

He foresees "personalised boxes" of medicines that cancer patients will take home.

"Hospitals will disappear and we'll have cancer hotels instead. Doctors, nurses and pharmacists will have new roles, and the cancer patients themselves will be empowered to make choices. They will become consumers, not patients."

But Sikora also warns that the cost of personalised medicines for all "will strain health-care budgets around the world".

At the same science festival, Dr Tom Shakespeare, of Newcastle's Policy, Ethics and Life Sciences Research Institute, warns against trying to make people "normal". A passionately articulate dwarf, he decries Soviet-era attempts to lengthen short people's legs, parents' decisions to have cosmetic surgery on their Down Syndrome children, and new cochlear implants which can help deaf people to hear.

"Many deaf people consider themselves not disabled at all but members of a language minority," he says.

When foetuses in Victoria were screened for Down Syndrome from 1993 to 2000, the number aborted because of the syndrome rose from 20 to more than 80 a year. Yet the majority of Down Syndrome babies are lost in pregnancy anyway. The main effect of the "choice" was to make parents feel guilty for doing actively what was quite likely to happen naturally in any case.

Overseas, it is already possible to test an artificially fertilised embryo for genetic defects by injecting sperm into an egg in the laboratory - before it has even been placed inside its mother's womb. Amazingly, when the embryo has grown to just eight cells, you can take one of those cells for testing and leave the other seven to grow into a normal, healthy baby. At that stage the cells are all totally "potent" and can develop into any cells in the body.

The head of northern region genetic services, Professor Ingrid Winship, has no doubt that this service will come here soon. But at present it is likely to cost $10,000, pricing it out of reach of all but the well-off.

Since 1969, all newborn babies in New Zealand have had four drops of blood taken from their heels in their first two or three days to test for what are at present seven rare and potentially fatal disorders.

The screening picks up about 40 out of the 55,000 babies born here each year - mostly with either cystic fibrosis, a mucus problem that can be treated with drugs and physiotherapy, or a thyroid gland disorder which can cause mental handicap unless the person keeps taking a thyroxin drug throughout life.

The National Testing Centre, based at Auckland Hospital, asked the Health Ministry early this year to add a further 30 tests, mostly for food-processing disorders, to pick up about 10 to 12 extra babies a year who need urgent treatment. The centre's director, Dr Dianne Webster, says the extra tests could be done for only the cost of a machine - about $750,000. The ministry is still considering the proposal.

Expectant mothers aged 35 or over, who have a higher risk of genetic mutations, are offered tests during pregnancy. "It gives families a choice," Winship says. "It's the parents' choice whether to continue with a pregnancy in the knowledge of a genetic disorder."

Her Auckland-based clinic has a waiting list of families wanting to check for mutations making them more likely to get certain inherited cancers, such as breast and bowel cancer. She says the clinic will only do these tests if a reasonable proportion of close relatives has had the disease. The free tests cost the state about $2 million a year in the northern North Island.

At present, apart from babies, the tests are usually limited to one disorder. But Winship says tests of multiple disorders on a microchip computer will soon be possible.

One test that is not yet common is for very rare disorders that can kill otherwise healthy young people through an "electrical fault" that makes the heart suddenly beat chaotically. Ben Frost, a Belmont Intermediate School student who died at 12 during a hockey game, had been told after three previous collapses that he had epilepsy.

In fact, he had a rare genetic mutation called long QT syndrome, which had a 50 per cent chance of being present in the other members of his family. If Ben's doctors had found it in time, he could have been given drugs to steady his heartbeat, or fitted with a defibrillator which would have shocked his heart into beating normally again when it went awry.

A former Birkenhead couple, Anne and Terry Guyan, lost two children to the same syndrome, three years apart. Daughter Denise and son Stephen died during swimming lessons soon after getting a vaccination that all children had at age 13.

The Guyans' only surviving daughter, Wellington journalist Claire Guyan, says no one paid any attention to what were later found to have been warning signs.

"It turned out that my brother had had a fainting episode the day before," she says. "He had been running, it was a hot day. People said it was 'just one of those things', as you do."

As with stomach cancer, the long QT mutations do not mean everyone who has them will drop dead at a young age. Both Anne Guyan and Ben Frost's mother, Denise Frost, carry the disordered gene, but have never had any symptoms.

A children's heart specialist at Green Lane, Dr Jon Skinner, says it is quite possible that heartbeat "chaos" was triggered in the two Guyan children by other factors such as their vaccination and puberty.

Skinner, Green Lane colleagues and Auckland Medical School researcher Mark Rees have used money from gambling machines through a Lion Foundation grant to start a registry of families with inherited heart disorders, and are willing to test people who have lost close relatives suddenly. But a study of sudden infant deaths in 10 families, funded by the Cot Death Association, has been stalled by an ethical dispute over whether parents should be consulted before using blood samples held at the National Testing Centre.

Another application to the Health Research Council last year to study sudden death in the 1 to 35 age group was turned down, along with 81 per cent of the applications the council received. Council chief executive Bruce Scoggins says he would like to have funded the study.

"They are good researchers and this is an ongoing problem," he says. "The problem is that there is not enough money. For every one that we funded, there were at least two others that international peer review said should be funded."

Skinner says the Green Lane cardiologists proposed a cardiac inherited-diseases service as part of a 10-point plan for heart services three years ago, but health authorities did not see it as a priority.

Auckland District Health Board communications manager Megan Richards says the idea was never formally put to the board, and would have to stack up against many other demands on a board with a $50 million funding shortfall.

So Rees and Jackie Crawford of Green Lane's pacemaker unit run the heart gene testing service largely in their spare time. Rees says they will have to give up in the next few months unless someone is willing to finance the cost of about $750 for each test.

"We could do so much," he says. "We have families who had people psychologically stressed for years wondering whether they are going to live or die, not being able to get on with their lives.

"We are desperate to turn this into a professional full-time thing, but we don't have the backing from the research councils and the health authorities. We are doing it anyway, hand-to-mouth. While bureaucrats are mucking about, people with treatable cardiac inherited disorders are dying."