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March 28, 2002


1.       Jumping genes make "designer" animals easy
2.       Should jumping genes be used in people?
3.       Nominee for health chief backs stem cell research


Jumping genes make "designer" animals easy

19:00 27 March 02
Exclusive from New Scientist

A bit of fly DNA might be about to turn the trickle of genetically modified
animals into a flood.  Biotech company Tosk of San Francisco says it can add
genes to mammalian cells with unprecedented efficiency with the help of
fruit fly DNA that can jump in and out of chromosomes.
The company's claims are being greeted with a mixture of enthusiasm and
scepticism by other biologists, who warn its results have yet to be
independently confirmed. "But if it works the way they claim, it's
revolutionary," says Tom Rosenquist of Stony Brook University in New York.
Introducing genes into mammals is laborious and expensive at present, so the
technique is only used for research and to create animals that yield
high-value medical products. But if making GM mammals becomes cheap and
easy, companies could soon be modifying everything from the farm animals
that produce our food to our pets. Tosk's method could even be used to
correct genetic faults in people.
Human gene therapy - the hopes and fears
At the moment, GM mammals are usually made by injecting naked DNA directly
into an egg. But the success rate is extremely low: to get just one GM
animal, a skilled technician has to carry out dozens of injections and then
implant the resulting embryos. An alternative is to start with ordinary
cells and then try to clone the few that integrate the extra DNA. But this
is not very efficient either.
Tosk's method cuts out this tedious manipulation, New Scientist has learned.
The extra DNA is simply injected into an animal's bloodstream. Within a
couple of weeks, it is integrated into a high proportion of cells in many
different tissues, says Tosk's chief executive Patrick Fogarty.
Since some sperm and egg cells are also altered, normal breeding can then
produce animals in which every cell carries the extra DNA. When mice are
modified by injecting DNA into their tails, Fogarty claims, 40 per cent of
their offspring on average carry the extra DNA - an amazingly high
Tosk's secret is jumping genes, or transposons, which are found in many
organisms. They are genetic parasites: bits of DNA with no function, merely
the peculiar ability to spread themselves around by hopping in and out of
DNA with the help of a "cut-and-paste" enzyme called a transposase.
A typical transposon consists of a gene that codes for a transposase flanked
by unique marker sequences. When the enzyme is produced, it homes in on the
markers, snips out the entire transposon and pastes it elsewhere in the
cell's genome.

Delivery system
One of the most active transposons is the P-element, found in fruit flies.
For decades, scientists have used it to make transgenic flies by replacing
the transposase gene with the genes they want to transfer. But nobody could
get it to work well in mammals.
Now Fogarty, who left Stanford University to start Tosk, says that by
tinkering with the structure of the P-element, his team can get it to
integrate into up to 80 per cent of mouse and human cells in culture. The
delivery system consists of two bits of DNA: one containing the gene to be
introduced, flanked by the marker sequences, the other containing the gene
for the P-element transposase (see graphic).
Trillions of copies of these bits of DNA, encased in fatty globules that
help them enter cells, are injected into an animal. The animal's cells then
start producing the transposase, which cuts and pastes the extra gene into a
random site in the cell's genome.
The transposase gene itself is not integrated into cells' DNA, but breaks
down after a couple of weeks. Once that has happened, the inserted bits of
DNA stay put.

Made to measure
Tosk has just launched a service to make transgenic animals, and a few
scientists have begun placing orders. "If it's true it's wonderful," says
biologist Laurence Bugeon of Imperial College, London, who has just got a
batch of mice from Tosk. Fogarty says they have also begun collaborations
with about a dozen corporate partners that will test the technique in goats,
cows and pigs.
So far, however, no details of the company's experiments have been
published, and it could be months before its claims can be independently
verified. Other scientists say that the company needs to do more experiments
to prove that gene integration is indeed happening through transposition.
Still, Tosk is not alone in developing transposons for gene delivery.
Published work using other transposons suggests that the technique might
also become a valuable tool for correcting genetic defects in people.

Sleeping Beauty
Right now, the main approaches in gene therapy research are to infuse naked
DNA into cells or to use viruses to add DNA to the genome. But naked DNA
survives only a short time, and there are obvious safety concerns with
viruses. Transposons could provide the best of both worlds: stable
integration without the dangers of viruses.
One transposon derived from fish, called Sleeping Beauty, has been used
successfully to deliver genes to the livers of mice with haemophilia (New
Scientist, 22 November 1997, p 11). But even in culture Sleeping Beauty
integrates at a low rate - just five to six per cent of cells. Tosk says its
transposon is about 10 times as efficient, an enormous difference.
Of course, there are major concerns
<>  that need to be
addressed if transposons are ever to become tools for gene therapy. "But if
you look at the general principles, it's a wonderful system," says Richard
Mulligan of Harvard Medical School. "Time will tell."
Sylvia Pagan Westphal


Should jumping genes be used in people?

19:00 27 March 02
Exclusive from New Scientist Print Edition

It is one thing to use jumping genes from flies to make transgenic animals,
but quite another when it comes to gene therapy in people. The idea of
having a bit of fruit fly DNA inserted into your cells is uncomfortably
reminiscent of the movie The Fly.

In principle, the added DNA should consist only of the desired genes flanked
by short marker sequences - so you would not have much fly in you. But this
DNA is inserted randomly. One fear is that it could land in the wrong place,
knocking out vital genes and making cells cancerous.

The chances of that are minuscule, says Perry Hackett of the University of
Minnesota. Only about 1.5 per cent of our DNA consists of genes, we have two
copies of most of them and cells usually commit suicide if they have a
serious defect. In all the gene therapy experiments that have been carried
out, there has never been any evidence of such problems, he says.

A more realistic worry, if Tosk's method is as good as the company claims,
is integration of a gene into the human germline. If the extra gene ends up
in a patient's sperm or egg cells, it could be passed on to any children
that person has.

Targeting organs

Regulatory agencies such as the US Food and Drug Administration do not allow
any gene therapy trials that might result in germline alteration. To
minimise the chances of this, Tosk's Patrick Fogarty says it should be
possible to target organs where the gene is needed, such as the heart or

But it might not be that easy. Even the relatively inefficient viruses
already used in gene therapy occasionally seem to find their way into gonads
(New Scientist, 14 March 1998, p 7). In 2000, the American Association for
the Advancement of Science concluded that it is "very likely" that some gene
therapy trials authorised in the US have already had unintentional impacts
on the germline.

Some argue that germline transmission is desirable, though. A person with a
genetic disease might welcome a cure that also protects their future
children. "Personally I think gene therapy without a germline component is
unethical," Fogarty says. "However, I wouldn't want any of the current viral
technologies used in the human germline."

The effects of random integration are more of a worry if the germline is
affected. A relatively minor mutation could have serious consequences if it
were present in all a person's cells.

Fogarty says, however, that Tosk is working on a way to get its transposons
to insert genes into particular sites in the genome. If the company really
can deliver an efficient way of targeting genes, it could undermine many of
the current arguments against germline gene therapy.
Nominee for health chief backs stem cell research
Financial Times
By Victoria Griffith in Boston
Published: March 26 2002 19:58 | Last Updated: March 26 2002 20:34

President George W. Bush extended an olive branch to the US scientific
community on Tuesday by nominating as head of the National Institutes of
Health (NIH) an administrator who favours embryonic stem cell research.
If approved, Elias Zerhouni, executive vice-dean at Johns Hopkins School of
Medicine, a centre for stem cell research, would occupy a position unfilled
for two years. The administration's failure to fill the job has caused
consternation among researchers who are concerned that the president is not
being properly advised on science issues.
The approval process may be controversial as abortion rights activists have
indicated they may oppose Dr Zerhouni.
Two other key posts - head of the Centersfor Disease Control and the head of
the Food and Drug Administration - remain unfilled.
Finding a replacement for former NIH director Harold Varmus has been a
challenge, since Mr Bush wanted to find a respected scientist who could work
within his strict guidelines on embryonic stem cell research.
The administration also announced on Tuesday Mr Bush's selection for the
surgeon general post - Arizona surgeon Richard Carmona. Dr Carmona inspired
a made-for-television movie by using a helicopter to rescue a person
stranded on a cliff in 1992. He was once involved in a shoot-out after
stopping to help victims in a car crash and served as part of the elite
Green Beret force in Vietnam.
If his nomination is approved by the US Congress, Dr Carmona would replace
David Satcher, former president Bill Clinton's appointment, who announced
last year he was leaving the post. Among the surgeon general's obligations
are the oversight of responses to bioterrorism.
Mr Bush has already asked for a boost in funding for the NIH next year to
more than $27bn (E30bn, #19bn).

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