'Crude and rude' GM condemned

A New Zealand researcher working in the US abhors the 'sloppiness' of inter-species gene transfer. SIMON COLLINS reports.

When David Williams expresses concerns about genetic engineering, he carries weight - because he does it himself.

Born at Kaikoura and raised on a Banks Peninsula sheepfarm where his brother still farms, Dr Williams is an adjunct professor at the University of California, San Diego.

He leads a team who are trying to inject a gene into the back of the eye to restore sight to about 5000 Americans and perhaps 100 New Zealanders with a rare genetic mutation called Usher Syndrome.

But he says his kind of "gene therapy", replacing a mutant gene with a normal one from the same species, is quite different from inserting a gene from a different species into a crop.

Last year, Dr Williams made a submission from San Diego against an application by Crop & Food Research to modify onions to resist Monsanto's Roundup weedkiller, saying the institute had failed to investigate all the changes that its experiments would induce in onions.

"I just abhor sloppiness," he said this month at his home in the eucalyptus forests behind San Diego, keeping an eye on his two young children playing in the garden.

"The problem with this GE approach is not GE per se - I do this stuff myself. It's the fact that they are going ahead with a crude-and-rude approach and throwing these things into the food chain."

Dr Williams' perspective is interesting because even now, 14 years after a 4-year-old Ohio girl with a severe immune deficiency became the world's first gene therapy success, there are still not many gene therapists around.

Only one gene therapy operation has been conducted on humans in New Zealand - carried out by Auckland University's Professor Matt During on two infants with Canavan disease, a fatal brain disorder, in 1996.

Professor During used the technique again last August to inject a gene into a man with Parkinson's disease in New York. Some colleagues called the experiment crazy because tests on monkeys had not yet been published, but patient Nathan Klein says on a website 10 months later that the symptoms of his illness have "improved 40 to 60 per cent".

In plants, genetic modification is usually done by injecting a gene into a single cell that is then grown from a seed into a plant which carries the new gene in all its cells.

In human beings, ethical considerations have held scientists back from such radical experiments. Instead, gene therapists aim to inject genes into specialised cells that carry out particular body functions.

Dr Williams and his team are targeting the photo-receptor cells at the back of the eye that capture light and translate it into an image for the brain.

Babies with Usher Syndrome - about one in every 20,000 - are born deaf and start going blind in their teens.

They start off learning sign language to get around their deafness, then lose the ability to see hand-signs and have to learn a new language based on touching different parts of the palms of their hands.

"It's very frightening for these people because they lose contact with the deaf community," Dr Williams says.

Gloria Campbell, a practice adviser with the Royal New Zealand Foundation for the Blind, works with about 20 Usher patients in Auckland. She says many of her patients are "in a constant state of crisis" as their sight deteriorates.

"To be able to stop that deterioration would be incredible," she says.

Dr Williams' team has found the faulty gene that causes the syndrome, and is now working with mice to try to inject good versions of the gene into the photo-receptor cells.

"The eye is a pretty good place to be progressing with gene therapy because it's an isolated system with a lot of cases of blindness caused by the loss of function of a single gene," he says.

"All you have to do is get the gene back in and you can replace function."

But it is not quite as easy as it sounds. After years of work, Dr Williams has not yet managed to inject the good gene directly into photo-receptor cells, but he has got it into another group of cells just behind the photo-receptors called the epithelial (outer layer) cells.

The technique involves a virus - a tiny infective particle made up of a string of genes so small that it can get into living cells.

"We put a good copy of the gene into the virus and inject it into that space between the photo-receptors and the epithelium. Each cell that is infected starts expressing [the new gene]," he says.

But Dr Williams has chosen a gene that is expressed only in the photo-receptors and the epithelium. Tests show it does not affect other surrounding brain cells.

Colleagues at Pennsylvania University, working on a different genetic eyesight fault, have restored sight to dogs that were born near-blind.

Both they and Dr Williams want to be more sure of their ground before they do trials in humans. What worries Dr Williams is that plant geneticists show much less restraint.

Like medical gene therapists, GM crop scientists sometimes use sequences from viruses to get new genes expressed in plant cells.

But unlike gene therapists, they insert genes that are typically expressed in all parts of the plant at all times. Tests with a simple plant last year showed that inserting one new gene affected three-quarters of all the plant's other genes.

"You do affect other genes when you slam a transgene in, but they are not checking on that," says Dr Williams. "They are not doing it because it costs money."

He says it would be much safer to target particular genes. For example, Crop & Food could use a Roundup-resistant gene that is expressed only when a growing plant is sprayed with weedkiller, and not when it is harvested later.

"Genes are expressed at different times of development.

"If you know what genes are turned on at particular stages of development, you find a gene that is turned on during that window of the plant's life when you want to spray," says Dr Williams.

"Then you don't have this foreign product - because after all, it is from a gene of a bacterium - in the human food chain."

But Dr Tony Conner, of Crop & Food's genetic engineering team, says there is no more reason to fear direct manipulation of plant genes by an inserted gene than there is to fear equally dramatic changes made by conventional breeding for thousands of years.

"Huge arrays of gene changes can be expected to occur as a result of gene transfer via traditional plant breeding," he says.

No one checks all those changes in detail every time a plant breeder grows a bigger carrot or a sweeter potato, so why should the genetic engineering of plants be treated differently?

"You have to put this into the context of what we need to know, as against what would be nice to know," Dr Conner says.

"With GM approaches, changes can be better recognised as being issues when you know exactly what you have transferred to a plant, as opposed to regular plant breeding."

He says GM crop scientists are working, as Dr Williams advocates, towards targeting the genetic changes they make in plants to affect only the genes that "turn on" at the appropriate time, such as when the plant is growing and being sprayed rather than at the time of harvest.

But food is different from medicines, Dr Conner says, so the regulatory standard that it should be "substantially the same" as existing foods is sufficient.

"With drugs, you are putting a very, very high dose of a specific compound into your body that is expected to have a specific biochemical effect.

"In those cases, you are generally trying to inhibit or strengthen some function and you can anticipate that there will be dramatic effects," says Dr Conner.

In contrast, most of the time we do not eat food to have any effect on our health at all, but simply "for pleasure and to fill our stomachs".

We are, therefore, much more willing to take risks with food.

"Just go to the Wild Foods Festival on the West Coast," Dr Conner says.

"The risks [with GM], when you come down to it, are no different from traditional plant breeding in terms of unforeseen indirect changes."

He does allow that "nutraceuticals" - foods designed specifically for health effects - need to be more tightly regulated. But again, that applies regardless of whether the product is "golden rice", with an extra gene that produces more vitamin A, or a separate vitamin pill made by non-GM means.

From across the perceptual divide, Dr Williams scoffs at golden rice. The extra vitamin A engineered into it would not be enough to cure widespread blindness in the Third World, he says.

The world already produces plenty of food - the problem is that it is distributed unequally.

But then from the equity point of view, he concedes, much the same could be said of his own work.

"Spending millions of dollars to develop gene therapy for blindness when you could save millions of lives by increasing sanitation in Third World countries - there is a parallel there. I'm as deep in this as anyone else," says Dr Williams.

"But we are not touting this as the way to feed the world."

Williams Lab

Nathan Klein

Crop & Food Research