The nature of genes

By SIMON COLLINS

Don Love's goal is to create a transgenic fish in which a fatal muscle-wasting disease can be turned on and off by a drug.

The Auckland University biologist aims to help people suffering from rare conditions such as Duchenne muscular dystrophy, which affects one in every 3500 boys from about the age of 3.

"It's an inexorable decline - it's very sad to see," he says.

"They become wheelchair-bound at about the age of 12. They have breathing problems. They die in their early twenties through respiratory or cardiac failure."

The disease is caused by a genetic mutation. Males who inherit it are usually unable to have children. Females do not suffer from the disease but can pass the mutation on to their sons.

To date, it has no cure. American scientists have created a version of the gene which can strengthen muscles - but they are still working out how to insert it into people.

They have also successfully modified the same gene in mice. But Love says "the mouse model" does not exactly reproduce the disease in humans.

He is now trying to reproduce it in zebrafish, tiny black-and-white striped fish from India which happen to have gene sequences which are very similar to humans'.

"The latest thinking is the more models the better," he says. "Comparative genomics helps us to see the underlying biological mechanisms."

He and his students have succeeded in changing the way the gene works in newly fertilised zebrafish embryos. But so far they have not been able to make the effect last more than a few days and the rapidly growing embryo soon recovers and grows normally.

Their next target is to make a more lasting change, and to find a hormone or some other chemical that can reverse the change - in effect, a cure for muscular dystrophy in zebrafish.

The zebrafish embryos that have already been modified, however, will not live to benefit . Having done their bit for science, they will hatch into tiny fry and be killed two to four days later.

Most are killed simply by putting them in a fridge. Love, who chairs Auckland University's animal ethics committee overseeing 100 animal experiments a year, says a slow chill is humane: "They drift slowly into unconsciousness."

Compared with AgResearch's experiments on genetically modified cows at Ruakura, Love's zebrafish research has been low-key.

It is easier to empathise with cows because they are more on our scale. We also worry about genetically modifying them because we drink their milk, and because their products are our biggest source of national income.

Despite all the fuss over the environmental and economic risks of genetic modification, there has been relatively little debate about the ethics of GM.

It's a huge subject. There are big ethical question marks over whether we should be pouring taxpayers' money into looking for new drugs for diabetes, for example, rather than investing that money into a more proactive public health system to help people to keep healthy in the first place.

But, especially in an agricultural country like this, one of the biggest ethical issues with GM is animal welfare.

Is it morally right to experiment on animals, whether cows or zebrafish, as "models" for human diseases?

And if the experiments succeed and AgResearch works out how to produce a protein in cow's milk that may benefit humans with multiple sclerosis, for example, is it then morally right to turn living creatures into "factories" for human pharmaceuticals?

The Royal Commission on GM recommended in 2001 that a Bioethics Council should be set up to develop ethical guidelines. This week the new council, chaired by Sir Paul Reeves, launched its first major public consultation on the central issue of putting "human" genes into other organisms.

As Environment Minister Marian Hobbs noted, the issue is complex because most of our genes are not, in fact, uniquely ours. Ninety-eight per cent of our genes are also found in chimpanzees, 90 per cent in rats and mice and 85 per cent even in Love's zebrafish.

In one of 15 "reflections" on the issue posted this month on the Bioethics Council's website, Otago University anatomy professor Gareth Jones comments: "The genetic code is essentially universal, in that all cells from all species usually contain much the same information ... In other words, genes cross the species barrier all the time.

"A protein like insulin is made up of 150 amino acids, of which only five differ between humans and pigs. Hence, if the DNA sequence of the pig gene is altered to make a human protein, what has been produced? Can the resulting protein be described as a pig gene or a human gene?

"Perhaps it would be better to refer to it simply as a piece of DNA."

Yet Auckland University physicist Dr Peter Wills draws a different conclusion from the same genetic facts.

"When we think of genes and other organisms, we should think in a way that emphasises our commonality with other species and extends appropriate privileges to them in recognition of our shared ancestry," he writes in another "reflection".

"On what basis do we completely prohibit any engineering of our own species but allow the genetic engineering of animals?"

GM technology has grown out of a scientific tradition that always has learned from animals.

In 2002, Love's ethics committee at Auckland University alone approved experiments on more than 10,000 animals, including "a few tens" of his zebrafish. (Most of the 500 embryos produced from each tank of zebrafish in a day are not counted in the statistics, because they are modified well before they hatch into independent "animals".)

Nationally, 40 animal ethics committees approved experiments on 263,684 animals, including 1510 that were genetically modified. Some 15,817, mostly mice, were recorded as undergoing "severe" suffering.

In Britain, 2.7 million animal experiments took place in the same year, including 700,000 using GM. In the world, the total is just over 100 million.

Controls on animal and human research are rather different. Research on humans is approved by independent regional ethics committees whose meetings are open to the public. Animal experiments in Sweden and the Netherlands are also governed by regional or national committees.

But in New Zealand, animal ethics committees are required only to have three outsiders, one each nominated by the SPCA, the Veterinary Association and a local body. The other members, who range from two in a small company such as Timaru's South Pacific Sera up to 10 at Auckland University, are appointed by the research institution that is being monitored.

These rules are under review. But at present, animal ethics committees do not have to disclose anything about their work publicly apart from the ethical codes they operate under and their statistics, which are published on a national basis without any breakdown by institution.

A Wellington insect scientist, Dr Michael Morris, has tracked down information about many approved experiments by searching the world's scientific literature. He believes many would never have been tolerated if the system genuinely reflected New Zealanders' ethical standards. For example, AgResearch and the dairy research institute Dexcel have both sunk tubes into the sides of cows to measure the ongoing effects of drenches and food additives in their rumen, the first stomach where they chew their cud.

Dr Christian Cook, the HortResearch scientist who announced in 2002 a new method of testing the blood of America's Cup sailors without the need for an actual blood sample, had earlier studied the brain by inserting tubes into the heads of 84 sheep.

Morris comments: "Animals were burned with a 'thermal stimulus' as well as shocked. A great deal of data on brain chemicals was generated from the experiment, but the authors themselves admit that much of this had already been found in other species."

Animals should have rights, too, he argues: "Mammals, birds and cephalopods (squid and octopus) show cognitive capacities indicative of beliefs, desires, emotions and an awareness of their own future.

"If humans are to be valued as ends in themselves and not just means to an end, then there is no reason not to include higher animals in that category."

Love concedes that any benefits for human health from his research on zebrafish, for example, will be in the very long term.

"Yes, at the end of the day it's a fish, and you're trying to convince Joe Bananas that if you tinker with this it will tell me about that," he says.

But, he says, the outcome of basic research is nearly always unpredictable. As a biologist rather than a medic, he is interested not just in potential human benefits, but also in how genes work in the fish themselves, and what that may tell us about the way nature works as a whole.

"It's to understand the nature of the biological pathways that operate in all of us," he says.

Dr William Rolleston of South Pacific Sera, a farmer as well as a scientist who chairs the Life Sciences Network, takes a practical view.

"Is it ethical to use animals for human benefit?" he asks.

"Yes of course it is, because every species uses other species for their own benefit. We are part of that natural world. We couldn't survive if we didn't use other species."

Even Green MP Sue Kedgley, who is promoting a bill to open up the animal ethics committees' work, is willing to genetically engineer bacteria to produce insulin to keep diabetic humans alive.

"Personally I don't have a problem with bacteria and fungi," she says.

"It's a matter of where you draw the line. Myself, I draw the line at fish and other sentient beings. I think fish can suffer in the same way as animals."

Most importantly, she says, the issue needs to be brought into the open and debated.

"There is a policy vacuum. Scientists have just been filling it and charging way ahead of what public opinion thinks we ought to be doing," she says.

"The Bioethics Council is going to have a debate about these issues, but in my view it should be more than just advisory.

"Once it reaches a conclusion, that should be setting a policy and that should be binding on all these animal ethics committees."

Per cent of human genes shared with:

Chimpanzee 98

Rat 90

Mouse 90

Zebrafish 85

Fly 36

Yeast 23

Worm 21

Thale cress (plant) 15

E. coli (bacteria) 7

* Source: American Museum of Natural History

Bioethics