ngin - Norfolk Genetic Information Network

20 January 2003


A little while ago Dr Richard Nicholson, editor of The Bulletin of Medical Ethics, made this comment on the record of gene therapy to date:

"Ten years ago we were being told that gene therapy was the greatest thing since sliced bread. Today its record stands at: Cures: nil. Deaths: 5.  Major adverse effects: at least a thousand."

Since then gene therapy appeared to have it's only real success when a fatal immune deficiency was apparently cured in nine out of eleven boys in France. But now a condition resembling leukemia has developed in the second of those boys (see item 2). As the New York Times comments, "The treatments in France had been considered the only unequivocal success for gene therapy after a decade of failures."

According to Dr. Daniel R. Salomon, associate professor at the Scripps Research  Institute and chairman of the F.D.A. advisory panel for gene therapy, what has emerged in France "definitely is not the way we would have written it out had we had our fantasyland going. But this is dealing with reality." (item 2)

The kind of dangerous fantasy land that has overtaken many scientists and others is reflected in the other 2 articles (items 1 and 3) which are about human germline therapy where genetic modifications are made to humans which will be passed on to all subsequent generations. It's revealing that the BBC piece (item 3) talks about germline engineering as if it is largely a technical issue.

For more on these issues:

1.Making a perfect child
2.Gene Therapy Trials Halted
3.Permanent GM changes 'bred into mice'


1.Making a perfect child

The Sunday Telegraph (Sydney) January 19, 2003

IF you're worried by the thought of eating a few genetically  modified corn chips, you'll be horrified by Gregory Stock's  vision of the future. This American scientist says we'll  eventually start churning out genetically modified humans  -- and the modifications could be huge. Take a recent  astonishing experiment with mice. Researchers changed just  one of the mouse's genes, and it grew up to have a much  bigger brain. And by changing single genes in flies and in  worms, for example, scientists have managed to double the  creatures' life spans. Now a man is not a worm, nor a mouse  for that matter. But we do have a lot in common with  animals. Indeed, researchers have just finished mapping the  mouse's full complement of genes, just as they did for  humans not long ago. And the shock was there are just a few  hundred genes that separate mice from men. Stock thinks  genetically modified people won't be as hard to make as many predict, and so we'll start seeing them sooner than we  think. The thought of GM kids sounds horrific -- but the  question is, will not genetically modifying our children be  even more horrific? If medical science is able to clip out  the genes that cause terrible diseases like cystic  fibrosis, for example, surely the parents who choose not to  have their kids modified will be the ones in the wrong.

 When science is able to alter the genes that set people up  for disease and other afflictions, what parent wouldn't  want their kids' genetic make up cleaned up? After all,  these modifications would simply be making their child  normal. And is a parent's caring going to stop when it  comes to making their children better than normal? If a  doctor can safely modify their genes so they have bigger  brains or live twice as long, how could a parent argue?  After all, the alternative is to deliberately make their  child dumber than they could, or maybe condemn them to an  earlier grave.


2.Gene Therapy Trials Halted

New York Times, January 15, 2003

The Food and Drug Administration yesterday suspended 27 gene therapy  trials involving several hundred patients after learning that a second  child treated in France had developed a condition resembling leukemia.

The agency said it was not aware that any of the patients treated in the  27 American trials had suffered illnesses similar to that of the infants  in France but was nevertheless taking precautions.

"We see no evidence that the subjects in these 27 trials are actually at  risk," said Dr. Philip Noguchi, acting director of the agency's office  of cellular, tissue and gene therapies.

The temporary halt, the largest such action involving gene therapy  trials, is yet another setback to the fledgling field, which usually  involves introducing healthy genes into patients to treat diseases  caused by defective ones. The field is still shaken from the death of a  teenager undergoing gene therapy in 1999 at the University of  Pennsylvania and from the first case of leukemia in an infant in France  last year.

The treatments in France had been considered the only unequivocal  success for gene therapy after a decade of failures. Nine of 11 young  boys treated for a fatal immune deficiency widely known as bubble-boy  disease were able to leave the hospital and take up nearly normal lives.  But now two of them have developed the condition resembling leukemia.

"The exciting thing was that it was working," said Dr. Joseph C.  Glorioso, president of the American Society of Gene Therapy and chairman  of molecular genetics and biochemistry at the University of Pittsburgh.  "The horrible thing is that a shadow has been cast over that success."

In September, after the first of the children in France was found to  have the leukemia-like disease, the F.D.A. halted three clinical trials  that involved a similar treatment for immune deficiencies. Yesterday it  decided to halt all trials involving the technique used in the French  trial, regardless of the disease being treated. That technique uses a  type of virus known as a retrovirus to ferry genes into blood-producing  stem cells.

The 30 trials halted represent about 15 percent of the 200 gene therapy  trials under way and half of the 60 trials involving retroviruses. The  other trials using retroviruses insert the genes into cells other than  blood stem cells. The trials involving stem cells are considered more  risky because those cells proliferate, and leukemia is a disease in  which blood cells proliferate out of control.

Some of the trials being halted are intended to treat AIDS and cancer,  Dr. Noguchi said. The agency will consider lifting the suspensions in  individual cases for these life-threatening diseases if doctors fully  inform the patients of the risk and then monitor them carefully, he said.

Retroviruses are only one of several types of viruses used to deliver  genes into cells. But they are considered both particularly promising  and risky because the genes they carry become a permanent part of the  target cell's DNA. That means that when the cells divide, the inserted  genes remain in the daughter cells. Without that permanent insertion,  scientists said, gene therapy might have to be performed over and over.

But scientists also knew there was a theoretical risk that a retrovirus  would lodge near a cancer-causing gene and turn it on. Scientists say  that is what happened in the first leukemia case in France. The cause in  the second case has not been announced but some scientists say they have  heard the cause is similar.

But until the second case, scientists believed that the risk was low.  There have been perhaps 40 or 50 trials involving more than 100 patients  in the United States that involved using retroviruses to insert genes  into stem cells, said Dr. Donald B. Kohn, professor of pediatrics at the  University of Southern California and a gene therapy expert at  Children's Hospital in Los Angeles. Most had limited or no success, but  none had caused a cancer-like complication.

"The big question is why are we seeing this all of a sudden in two  patients in this trial but not all these previous patients?" said Dr.  Kohn, who was conducting two trials affected by the F.D.A.'s suspension.  He said one explanation could be that gene transfer has become more  efficient. Another is that there could be something specific to the  disease treated or to the gene used in the French experiment.

The American Society of Gene Therapy, which endorsed the F.D.A.'s  precautionary measure, said yesterday that it would set up a committee  to study the situation. The gene therapy advisory committee of the  National Institutes of Health will meet on Friday to consider the  situation, and an F.D.A. advisory committee will meet on Feb. 28.

Scientists said the new problems would not derail gene therapy because  the risks had to be balanced against the benefits. In this case, they  said, nine infants were virtually cured of a terrible disease. Indeed,  after the first three trials were suspended in September, an F.D.A.  advisory panel recommended resuming those trials on the ground that the  benefits outweighed the risks. The trials had not yet restarted.

Dr. Noguchi said the F.D.A. learned of the second French leukemia case a  month ago but did not act until yesterday because it wanted to study the  situation.

"We know the impact of F.D.A. taking an action like this," he said. "We  didn't want to do this without doing a very thorough evaluation of all  the risks and benefits."

Dr. Daniel R. Salomon, associate professor at the Scripps Research  Institute and chairman of the F.D.A. advisory panel for gene therapy,  said the F.D.A. was right to be cautious. "This definitely is not the  way we would have written it out had we had our fantasyland going," he  said. "But this is dealing with reality."

Dr. Salomon and Dr. Glorioso said there were techniques that could make  gene therapy safer.

Dr. Glorioso described the setback as "bumps in the road that happen  when you develop new therapies." He added: "I don't think it will kill  the field. I think it will cause us to work harder and engineer our way  out of the problem."


3.GM changes 'bred into mice'
The technique can "silence" genes
BBC NEWS, Monday, 20 January, 2003

Scientists may have found a new way of introducing genetic changes which are passed from parent to child.

But there are still many obstacles to be crossed before a way can be found to eradicate a genetic illness completely from both the patient and subsequent generations of their family.

Researchers now know much more about the function of thousands of genes found in every human cell.

In some people, mutations in certain genes may cause a malfunction in the cell, and the body at large, leading to disease.

The idea behind conventional gene therapy is to find a way to reduce the effects of the errant gene by inserting new versions that work properly.

Handed down

In humans, the "germline" of genetic information passed from parents to child can be found in the sperm and the egg.

In order to manipulate the genetic fate of the child - and generations to come - either these "germ cells" would have to be altered, or the child itself modified in the very first days of its existence in embryo form.  In the latest study, scientists have found a novel method of doing this in mice.

They are using a technique called RNA interference, which can switch off a gene or reduce its activity - stopping the cell from behaving in a certain way.

They introduced the change into "stem cells", extracted from early mouse embryos, then injected these genetically-modified cells into the target mouse embryos.

They found that not only were the changes taken up in these animals, but also in many of the first generation of their offspring.

Long way off

Despite the effectiveness of the therapy in these animals, treatments for humans are still on the distant horizon, and the new method may not prove suitable.

Mice have embryonic stem cells which can play a role in the creation of every tissue in the body - humans do not.

Dr Maggie Dallman, from Imperial College London, said the research, published in the journal Nature Structural Biology, was "very exciting experimentally".

However, she said: "If you are talking about changing the human germline, then this is not necessarily the method I would choose to do it."  However, in the meantime, the technique could provide another option for scientists to examine the consequences of tampering with the genes of experimental animals, perhaps speeding up the process of producing human therapies.

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