Polishing Up Your Genetic Inheritance

By Judy Siegel-Itzkovich

The tragic death of a young American from gene therapy will not hinder explosive development of the field over the next few years, US experts told a recent symposium in Jerusalem.

The death last September of an Arizona teenager resulting directly from gene therapy sent shock waves through the gene-research community. Some were concerned that this first death might halt extensive research in the field - some 400 clinical trials worldwide aimed at curing a variety of diseases.

Eighteen year-old Jesse Gelsinger suffered from a mild form of a rare metabolic disease which impairs the body's ability to rid itself of ammonia. He was given an infusion of genetically engineered viruses to replace a defective gene preventing him from producing a necessary enzyme.

Jesse himself was healthy. He took medication for his condition - diagnosed when he was two - and avoided protein foods. He volunteered for gene therapy in the hope that the research would discover a cure for others more severely afflicted.

But his condition deteriorated rapidly, and he died four days after the infusion. An autopsy directly linked his organ failure to the gene therapy. US federal officials sent letters to more than 100 scientists conducting clinical trials with similar viruses asking them to report any evidence of trouble.

Despite the heartbreaking incident, US geneticists and gene therapists who attended a recent Hebrew University symposium on "Genetics and its Impact on Society" were optimistic that Jesse's case, however tragic, would not deter scientists and physicians from developing and using gene therapy.

The event, open to the public, drew hundreds to Jerusalem's Wise Auditorium on the HU's Givat Ram campus. To help mark its 75th anniversary, the university brought in five genetics research leaders: Harvard University gene therapy expert Prof. Richard Mulligan; Stanford University human genome project expert Prof. David Cox; Cornell University plant genetics expert Prof. Charles Arntzen; University of California geneticist Prof. Paul Rabinow; and Lancaster University fertility and cloning expert Dr. Sara Franklin.

Princeton University's president, Prof. Harold Shapiro, who is a bioethics expert and philosopher rather than a scientist, also presented his views on biological manipulation.

The event was organized by HU geneticist and Israel Prize winner Prof. Howard Cedar, who noted in his introduction that "each of us starts off life with a genetic inheritance. Some will gain from it, and some will be harmed."

One person's genes can doom him to a short life or to disruptive or abnormal behavior, he said, while another person's can be a blessing.

Mulligan predicted that gene therapy for immune system diseases, including cancer, would be "definitive" within five years. Great progress, he said, will also be made for hemophilia, a heriditary condition in which blood cannot clot, and for other disorders that cause a great deal of damage.

Within two decades, he continued, analyzing a patient's genome and performing genetic repair or replacement of a defective gene will become routine.

"Despite the one tragic death, there will be a great explosion of gene therapy around the world," he said.

Successful gene therapy developed by French researchers recently changed the lives of two infants, aged eight and 11 months, who were confined to a germ-free plastic bubble because they had been born with severe combined immunodeficiency (SCID), a life-threatening disease inherited on the X chromosome. Usually, SCID patients must live in such tightly controlled environments until they can undergo a bone marrow transplant.

According to a report in the April issue of Science, the researchers began treating the infants by harvesting bone marrow and sorting from it a set of blood stem cells.

After a bath in a growth factor in containers coated with a fibronectin fragment - a threadlike protein encouraging efficient gene transfer - the cells were infected with a retrovirus carrying the replacement gene. The cells were then transplanted back into the patients without any prior drug treatment.

The normal gene quickly proliferated, "unblocking" the development of other immune cells and restoring the immune system to normal function.

In the SCID cases, cells with the normal gene seemed to enjoy a significant selective advantage, multiplying rapidly until their numbers overwhelm their mutated cousins. The infants' restored normal immune system has lasted over eleven months without side effects, says study co-author Alain Fischer of the Hospital Necker in Paris.

Mulligan said at the symposium that one difficulty in gene therapy research is the need for large amounts of money that only private companies can afford. In addition, researchers "sometimes move too quickly, but it's hard to jump over biological roadblocks."

Mulligan also warned against "superficial scientists who know a little about a lot of things rather than a lot about one thing."

Additionally, some gene therapists lack background in virology and other vital fields. "You need to train people without losing their biological roots... you need a lot of money and effective people" to do the work.

Cox of Stanford noted that 99.9 percent of all genes are shared by all humans, so differences between blacks, whites, and Orientals, or Australians and Alaskans, are extremely small. These differences are very ancient, he stressed.

"Genetic variation comes from hereditary mutations in the DNA of germline cells (eggs or sperm). One of the nucleotide base pairs changes in replication, and it then remains forever and is passed down to subsequent generations.

"It involves normal replication of DNA. You need a really good Xerox machine to replicate so many components. Some are bound to be copied wrong; the mutation could be a beneficial or a harmful one.

"Each person with such a mutation has a 50-50 chance of passing the change on to its child; if it's not passed on, it's lost."

Cox explained that it takes about 400,000 generations for any DNA change to appear in more than one out of 100 living persons, thus becoming a "polymorphism" that can spread to everyone.

"The mutations we see today first appeared millions of years ago. These predate various ethnic groups; they even predate the Jews, he added with a smile to an appreciative audience.

Diabetes, arthritis, and other common human diseases probably result from multiple genes that underwent changes in very ancient times.

The Human Genome Project - which is mapping human genes with all the DNA base pairs in sequence - will bring important benefits, Cox continued, but it will not solve everything, or, for example, tell us which genes are present only randomly and not responsible for certain diseases.

Arntzen of Cornell wowed the audience with his disclosure that genetically engineered potatoes may pave the way for a cheap vaccine against diarrheal diseases in children throughout the developing world.

The raw potato cubes are genetically engineered for a protein that stimulates antibody production against these diseases - the major killer of children in the Third World - and appears to reduce their severity.

While various conventional and genetically engineered vaccines are available in the West they are not affordable in places where the average person has an annual income of less than $400.

"We can't give all children raw potatoes, and heating tends to destroy much of the useful protein,' he said. "We think that bananas will eventually be the best plant-based vaccine, but it takes years to develop them."

Arntzen added that tomatoes, which grow quickly and can be eaten raw, also offer great potential.

Shapiro, who declared he was speaking as a bioethicist and not as a scientist, explained the general public's anxiety about gene therapy and genetic food engineering.

"Change is naturally accompanied by high anxiety... Laymen who oppose these things are not Luddites who are against change as a matter of principle," he said; they are less confident in others' competence to do things properly, and they're not sure where science is headed.

In conclusion, Shapiro urged scientists to reach the general public through an informed media, help the public deal with their anxiety, and explain the need for public support for research.

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