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May 2006 Updates

Mice Deaths Are Setback in Gene Test

By Andrew Pollack
New York Times
May 25, 2006

A large number of mice died unexpectedly in a test of a new technique for inactivating genes that has been widely proclaimed a breakthrough, scientists are reporting today.

The finding could give rise to new caution about the technique, called RNA interference, which is already widely used in laboratory experiments and is starting to be tested in people as a means of treating diseases by silencing the genes that cause them.

But Dr. Mark A. Kay and colleagues at the Stanford University School of Medicine report today in the journal Nature that the technique, also called RNAi for short, caused liver poisoning and death in mice.

"It's a very striking result — all of the fatalities observed and the toxicity, which was unexpected," said Timothy W. Nilsen, director of the center for RNA molecular biology at Case Western Reserve University in Cleveland. "It's really a note of concern for rapid therapeutic development of RNAi."

But Phillip Zamore, an RNAi expert at the University of Massachusetts, said the Stanford scientists had used a variation of the technique that was "no longer state of the art" and required a very high dose. The tests already conducted in people involve a different technique and lower doses, said Dr. Zamore, who is a co-founder of Alnylam Pharmaceuticals, a company in Cambridge, Mass., that is developing drugs using RNAi.

Dr. Kay himself said he thought the findings were "not a showstopper by any means" for the field. "It's like any drug," he said. "The toxicity depends on the dose."

RNA is the chemical cousin of , which encodes hereditary instructions in genes. RNA was once thought to be a mere messenger in the cell. But in a rush of discoveries over the last few years, scientists have found that RNA plays a more active role in controlling gene activity.

They have found that cells make tiny snippets of RNA, called microRNA, that silence particular genes. And they have learned how to harness that natural mechanism to turn off any gene of their choosing by inserting the proper piece of RNA into cells.

But Dr. Kay said his experiment showed that if too much interfering RNA was put into a cell, it could overtax the cell's ability to process its own microRNA. "The good news about RNAi is that it uses the cell's machinery to do its work, and that is why it's so effective," Dr. Kay said. "The bad news about RNAi is that it uses the cell's machinery to do its work. If you overload the system, you hijack the machinery from performing its normal duties."

Dr. Kay and his team, led by a postdoctoral researcher, Dirk Grimm, wanted to cure mice of B, not to kill them. They induced RNA interference in the mice's liver cells, intending to silence one of the hepatitis major genes.

In some cases this worked, and the virus was suppressed without side effects. In other cases the mice got liver poisoning, and some of them died.

The researchers tried the same thing in mice without hepatitis and then they tried using RNA interference to turn off different mouse genes.

Of 49 different RNA snippets meant to shut down six different genes, 36 caused liver injury and 23 led to death within two months. The RNA at the highest concentration was most toxic.

But some scientists said the problem appeared to be related to the technique used by Dr. Kay, which is a type of gene therapy. The Stanford team put DNA, not RNA, into the mouse liver cells. The DNA became part of the mice's genetic makeup and the mouse cells then produced the gene-silencing RNA, which was carried out of the nuclei into the body of the cells.

The scientists hypothesized that a protein that transports RNA out of the nucleus became overloaded.

The other technique is to put the interfering RNA itself into cells. That RNA does not need to be transported out of the cell nuclei, so that transporter protein would not be overloaded, some scientists said.

"These data really represent the fundamental limitations of gene therapy, not of RNAi," John Maraganore, chief executive of Alnylam Pharmaceuticals, said of the report in Nature. The company has already reported that it safely tested a nasal-spray RNA drug intended to treat a respiratory infection, on 65 healthy volunteers.


Rise in Rate of Twin Births May Be Tied to Dairy Case

By Nicholas Bakalar
New York Times May 30, 2006

[Monsanto has always claimed that its bovine growth hormone (known variously as rBGH, rBST and bovine somatotropin), injected into cows to make them give more milk, would have no effect on humans drinking the milk. Now a study indicates that women who drink Monsanto-modified milk (about 1/3 of all milk in the U.S.) are five times as likely to give birth to twins (compared to those drinking normal milk). Twin births can endanger the health of both the mother and the babies. - Rachel's comments]

American women who eat dairy products appear to be five times as likely to give birth to fraternal twins as those who do not, according to a new study, and one explanation may lie in dairy products from cows injected with synthetic growth hormone.

Dr. Gary Steinman, an assistant clinical professor of obstetrics at the Albert Einstein College of Medicine, reached that conclusion by looking at the medical records of 1,042 mothers who were vegans consuming no dairy products and comparing them with those of mothers who regularly ate dairy products.

His findings appear in the May issue of The Journal of Reproductive Medicine. Eating dairy products increases blood levels of insulinlike growth hormone, or I.G.F., and it is this increased hormone level that is associated with increased rates of multiple ovulation.

In a study published in 2000 and cited in the findings, vegan women had concentrations of I.G.F. that were 13 percent lower than those in women who regularly consumed dairy products.

Multiple births are associated with increased health risks for mothers and infants, but Dr. Steinman said he was not prepared to use these findings as the basis for advising women about diet before pregnancy.

"Since this is the first time diet has been implicated in an important role for determining twinning rate," Dr. Steinman said in an e-mail message, "it must be confirmed by others before rigid recommendations can be made concerning health care."

Insufficient diet in general lowers the rate of twin births, but Dr. Steinman said he had found evidence that the rate was directly related to levels of growth hormone.

"The more I.G.F., the more the ovary is stimulated to release additional eggs at ovulation," he said.

Animal studies, in rats and mice as well as in cattle, have convincingly demonstrated that increased serum levels of growth hormone are associated with increased ovulation.

All cow's milk has bovine growth hormone in it, naturally produced by the animal's pituitary gland. Many dairy farmers inject their cattle with recombinant bovine somatotropin, a synthetic version of the naturally occurring hormone. This increases size and milk production, but it has another effect: cows with higher growth hormone levels produce more twins.

The consumption of any dairy products increases blood levels of insulinlike growth hormone in humans, and consuming milk from cows that have been injected with synthetic growth hormone can have a correspondingly larger effect.

About one-third of American dairy cows are in herds where the hormone is used, said a spokesman for Monsanto, the only manufacturer of synthetic bovine growth hormone in the United States.

The evidence that eating dairy products increases the chances of multiple ovulation is suggestive, but not conclusive. Many factors, dietary and other, affect the rate of twin births. A study this month in Lancet, for example, suggests that the B vitamin folic acid may increase the survival of embryos in in vitro fertilization procedures, resulting in more twin births.

Fraternal twins run in families, so genetics also plays an important role. And the recent rise in the birth rate of twins is at least partly attributable to delayed childbearing, as older mothers are more likely to have twins.

The rate of twin births has also increased significantly since 1975, when assisted reproductive technology came into wide use. But these factors alone, Dr. Steinman said, do not explain the continuing increase in the rates in the United States since 1994, when recombinant bovine somatotropin was approved for sale.

In 2003, the United States had 3 sets of twins per 100 live births -- more than twice the rate of Britain, where growth hormone injection is banned. (Triplets and higher multiple births raise this figure to 3.18.)

Dr. Steinman suggested that one significant reason for the large difference was the recombinant bovine somatotropin.

"I am not claiming to be the first to show that variations in dietary amounts can affect the twinning rate," Dr. Steinman said. "What is new is specifying what in the diet may have this effect and how."

Source: 060530.htm

Diet Linked to Twin Births
May 22, 2006

Over the last 30 years, the number of twin births has nearly trebled. This rise seems to have followed the introduction of in vitro fertilization and a preference for having children later in life. But in the mid-1990s, doctors began limiting the number of embryos transferred in the course of in vitro fertilization and still the proportion of twin births rose. Now new research seems to show that bovine growth hormone in the food supply may be responsible.

Using data obtained from mothers by way of questionnaire, physician Gary Steinman of the Long Island Jewish Medical Center and his colleagues compared the number of twin births from moms who consumed meat and/or milk and those who consumed no animal products at all. They found that the omnivores and vegetarians were five times more likely to have fraternal twins than the vegans.

In a report published in the current issue of the Journal of Reproductive Medicine, Steinman argues that insulin-like growth factor, a protein released by the liver in response to growth hormone, may be the reason.

Studies have shown that the protein increases ovulation and that it persists in the body after entering via digested food, particularly milk. Drinking a glass of milk a day over a 12-week period raised levels of the protein in the body by 10 percent. Vegan women, it turns out, have 13 percent lower concentrations of it in their blood.

Steinman observed in the May 6 issue of The Lancet that although the twinning rate in the U.K.--where bovine growth hormone is banned--rose by 16 percent between 1992 and 2001, it increased by 32 percent in the U.S., where the substance is not banned. Of the new work he says: "This study shows for the first time that the chance of having twins is affected both by heredity and environment or, in other words, by both nature and nurture."


Keeping Tabs on Rogue GMOs

By Simon Terry
New Zealand Herald
May 22, 2006

Conditions for the international trade of genetically modified organisms (GMOs) are to become tougher as a result of changes to the Cartagena Biosafety Protocol.

Buried in the diplomatic language added to this United Nations agreement is a shift in the rules on food labelling that has deep ramifications for GM food cultivation.

The protocol will ultimately require sufficiently detailed labelling of GM content in food exports to make it the norm for GM crops to be strictly segregated from conventional export crops.

While a number of richer nations already have import requirements for identifying GM content, the protocol provides for their wider application to developing countries, and is likely to pave the way for a de facto global standard for labelling.

The success of these negotiations puts the protocol back on track to deliver an international liability regime governing shipments containing living GMOs.

The protocol regulates the international shipment of living GMOs and its central purpose is the protection of biodiversity and human health.

The new rules contribute to this by requiring identification of unintended GM content in shipments of conventional food.

Importing countries can then determine if they wish to prevent or limit the unintended release of GMOs through a process of informed consent in advance.

The labelling issue has, however, been a major point of contention since negotiation of the protocol began a decade ago and its final text, agreed in 2000, in effect postponed a real solution.

When a way forward was attempted last year, New Zealand and Brazil vetoed the proposed arrangements - changes required to make the agreement operational.

The recent negotiations thus became something of a do or die for the protocol, as a failure to reach consensus on labelling was likely to have resulted in individual countries going their own way to protect their borders.

Brazil, the host country, had rethought its stance and the compromise position it put forward - primarily a delay in implementing some aspects - gained early backing from other parties.

However, the New Zealand delegation, led by the Ministry of Foreign Affairs and Trade, indicated that its position had not changed.

While it agreed with labelling intentional GMO content in food, New Zealand said it remained steadfastly opposed to labelling GM content that was unintended - it did not want to label for "actual content".

Concern over New Zealand's stance prompted the heads of two other delegations to take the unusual step of speaking to journalists while the negotiations were in progress.

Leading African representative Dr Tewolde Egzhabier, of Ethiopia, said: "New Zealand's position is freezing the whole of the negotiations."

The EU couched its comments in more diplomatic terms, but the message was the same - New Zealand was not supporting the Brazil compromise and other countries were struggling to understand why.

New Zealand was not the only country raising difficulties - Peru, Paraguay and Mexico also had issues. However, it was the one many countries were most concerned about.

Then, on the last day, New Zealand dropped its objections, the concerns of the Latin American counties were attended to, and the hammer fell without dissent.

The protocol establishes the framework for nations to require that any GMO contamination in a shipment is identified and labelled in accordance with an importing country's minimum standards.

Although there are limitations for the next six years on the scope of GMOs for which labelling can be required, these are intended to expire once the phase-in period is over.

Each of the 132 countries that have ratified the protocol determines its own threshold standards for what triggers the labelling requirement. But exporters will want to produce to just one standard of purity, so the strictest major importer will tend to act as a ratchet setting standard for all.

The EU, which is New Zealand's largest food export market, already has the bar set at 0.9 per cent maximum GM content, and other countries can now use the protocol to readily impose standards that are tougher.

As a result, any country thinking of newly permitting GMO cultivation will most likely allow GM crops only if they are strictly segregated from conventional export production.

Segregation can be very costly, where it is technically achievable.

More costly, however, is not properly segregating, given the strength of consumer resistance to GM foods.

Wholesale buyers in markets such as Japan and Western Europe have zero tolerance for GM contamination and continue to reject food products with any detectable level of GMO content irrespective of whether it triggers labelling requirements.

Who pays for segregation or product rejection thus becomes a key question - one the protocol is also poised to influence. The next major change will be an international liability regime intended to allow importers to gain redress for harm caused by a living GMO.

For this to work fairly for conventional farmers that suffer GMO contamination, each country needs to have domestic law that ensures that claims ultimately rest with those producing the GMOs.

The protocol is therefore likely to put into sharp focus New Zealand's ill-founded liability law that essentially absolves from claims anyone who uses a GMO consistent with an ERMA approval.

Premium export markets will leave no place to hide from GMO contamination and those who cause losses for conventional farmers should not be able to hide from the financial consequences.

* Simon Terry, executive director of the Sustainability Council, attended the third meeting of the parties to the Cartagena Biosafety Protocol in Brazil.

Source: 027AF1010F


GM Organic Contamination Stokes EU Controversy

Food Production Daily, France
May 24, 2006

The threshold for the contamination of organic products with genetically modified organisms (GMO) was one of the most controversial issues discussed by EU agriculture ministers this week.

The new EU regulation on organic production was discussed for the first time on Monday. At least 10 Member States at the Council called for the GMO threshold of 0.9 per cent for conventional products to be formulated much more strictly for organic agriculture. Critics of gene technology, including Greece, Italy and Austria, were particularly vehement.

EU Agriculture Commissioner Mariann Fischer Boel countered that the burden on organic agriculture in the EU must not be increased unnecessarily. She argued that a GMO threshold of less than 0.9 per cent would increase costs in organic agriculture.

She said that the situation should not be made more difficult for such a promising sector.

In addition, Austria's agriculture minister Josef Proll, the current president of the EU agriculture council, called for low GMO threshold for conventional agricultural seeds.

Two further meetings have been scheduled to iron out these differences.

"The two further meetings of the council working group that have been scheduled now make it possible for the Finnish Presidency to reach conclusions before the end of the year," said Austria's agriculture minister Josef Proll, the current president of the EU agriculture council.

Some points were less controversial. The Member States agree that, with regard to organic agriculture, the Commission should not have greater influence than it has hitherto.

All the Member States took the view that details of production technology should continue to be deliberated on the regulatory committee and not on the management committee, where the Commission has the final word.

In addition, the ministers unanimously approved conclusions setting two main tasks for the EU Commission. Firstly, environment commissioner Stavros Dimas is to submit a proposal for a GMO threshold for conventional seeds.

Secondly, the Commission should examine whether additional rules from Brussels on coexistence are appropriate. On this point, the Commission has agreed to compile and evaluate studies on the various national liability regulations and guidelines on segregation of GMO and conventional crops in the Member States by the end of June.

However, the Commission made no pledge on the proposal for seeds, especially as the Commissioner responsible was not present. Proll explained that the threshold for seeds should be kept as low as possible.

"We shall be very careful to ensure a sensible solution to this problem is found," he said. "Today's policy debate on organic products has, without doubt, clearly shown that organic agriculture is considered very important for the future."


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