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The gene genie is out of the bottle

MagazineMay 2002 (Vol. 13 Issue 2)The gene genie is out of the bottle

One of my earliest suspicions of the value of good intentions came to me when I was a kid growing up in Honolulu, Hawaii

One of my earliest suspicions of the value of good intentions came to me when I was a kid growing up in Honolulu, Hawaii. We avoided playing in most of our large backyard because of the risk of meeting up with the dreaded huge and horrible African snails, absolutely the last thing on earth you would want to trod on.

I remember asking my father: if they are African snails, why are they here? He told me that, in the early days of Hawaii as a US territory, agricultural exports were a major industry, requiring, among other things, modern methods of agricultural pest control.

One of these pests was a little plant-destroying snail, and the African snail was introduced into Hawaii because it fed on its smaller relations. So, within decades, one localised small-snail problem was replaced by a much larger one extending across the entire state.

So much for good intentions.

With the cracking of the DNA code in the Human Genome Project, scientists will soon be able to identify and sequence the 30,000 genes that supposedly make you who you are.

There's now a new field of study - pharmacogenomics - or how an individual's genes affect his response to drugs. With this, scientists believe, comes the promise of more powerful medicines that are safer, target-specific and tailor-made for the given patient.

In Vancouver, Chromos Molecular Systems has pioneered man-made chromosomes that can be mass-produced for experimental use by other labs. So far, trials have demonstrated that cells readily accept these new chromosomes, copy them and pass them on during cell division. It is eventually hoped that these new chromosomes will manufacture complex drugs that can't be mass-produced by today's technology.

Scientists are even working to create vaccines made of DNA or RNA that will work as well as current vaccines are purported to, but supposedly with none of the risks.

The idea behind genetic immunisation is much the same as in current immunisation - to trigger an immune response to a disease without actually causing the disease itself. The difference is that the genetic vaccines use plasmids, small rings of double-stranded DNA derived from a bacterial pathogen, that carry the genes to produce antigenic proteins, but exclude those genes that cause disease. This application of gene therapy is already undergoing early trials in humans.

Other forms of gene therapy have similarly used a modified 'harmless' virus to carry modified 'healthy' genes. In 1990, a three-year-old girl in Cleveland, Ohio, made history when doctors infused her with genes to produce ADA, an infection-fighting enzyme that she lacked. In a Philadelphia clinical trial in haemophiliacs, gene therapy allowed them to reduce the amount of synthetic blood-clotting drugs they needed to take.

Yet, however good these intentions and the theories behind them, gene therapy has also suffered a number of setbacks. In 1999, 18-year-old Jesse Gelsinger died of multiple organ failure after receiving gene therapy to correct a rare genetic defect of the liver - ornithine transcarbamylase (OTC) disorder - that made his body unable to clear ammonia from the bloodstream.

Jesse was one of 18 patients in a clinical trial of gene therapy carried out by the University of Pennsylvania's prestigious Institute for Human Gene Therapy (IHGT). Doctors there had infused him with close to one trillion particles of AAV (adeno-associated virus), a highly invasive - and therefore ideal - gene-transport system.

His death came as a complete surprise. Indeed, it was unnecessary. Jesse had a safe alternative: the usual treatment for OTC is to take an ornithine substitute, such as L-citrulline, and to restrict dietary protein.

After Gelsinger's death, US health officials heard of at least six other unreported deaths involving gene therapy. One Toronto brain-cancer patient, James Dent, died unexpectedly in 1997, two days after beginning the second stage of gene therapy.

It is evident that progress lies in trial and error; indeed, we learn more from our failures than our successes. But what is worrying about all these trials and errors is the arrogance with which they are being pursued. As said of 'John Hammond' in Jurassic Park, because scientists and researchers now can, they aren't stopping to ask if they should.

And in the headlong rush to be the first to discover the next major 'cure', are scientists willing to take responsibility for dealing with the consequences? In the case of Jesse Gelsinger, the university has since taken steps to improve patient safety in all such experiments - a little late in Jesse's case. And, although all human trials by the IHGT have been stopped, this will not end all such human experiments at the university.

There's little doubt that the Human Genome Project has given scientists a whole new box of toys to play with. Yet, although gene therapy in principle sounds miraculously elegant and simple, life is a lot more complicated than many scientists would like to believe.

Playing God must involve more than playing with genes and delivering designer DNA into the nucleus of a cell - whether animal, vegetable or human. There are long-term ethical and moral issues that need to be addressed. But to the eye of many scientists, the world is just one giant laboratory, and every living thing in it is a guinea pig to be prodded, tested, modified and improved - all of it to make life better. The intentions are always good, but we all know what that's worth, don't we?

Sharyn Wong

Sharyn Wong is production editor of What Doctors Don't Tell You.


Dad taken home to die with dignity and without doctors

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