GENET archive


2-Plants: Update on GE pharma tobacco

                                  PART I
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TITLE:  Fighting against cervical cancer, tobacco raises hope
SOURCE: Checkbiotech, Switzerland, by Katharina Schoebi
DATE:   26 Jun 2005

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Fighting against cervical cancer, tobacco raises hope

Papillomaviruses (PV) are the causative agents for many cancers. Many
women in developing countries suffer from these harmful viruses.
Therefore, inexpensive and easily administered vaccines are of great need.

Human papillomaviruses (HPV) infections are the most common and
widespread sexually transmitted disease in the world. There are more than
150 different human papillomaviruses, split into two groups (high- and
low-risk HPVs) and distinguished by different numbers.

HPV16 are known to cause cervical cancer, from which a quarter of women
from developing countries suffer. However, also some intestinal
carcinomas have been linked to HPVs. Therefore, there have been several
research projects concerning the development of a prophylactic vaccine
against the cancer-causing types of HPV.

Some vaccines against animal papillomaviruses have been used
successfully. Since animal PV has some features in common with human PV,
such as similarities in its genome, proteosome, structure and
pathogenicity, researchers are enthusiastic about the possibility of
generating a prophylactic vaccine against HPV, too. However, HPV are
strict species-specific that depend on the maturity of cells called
squamous epithelia. Thus, they cannot grow in animals or in vitro, a fact
that has hindered the generation of a vaccine.

Due to recent developments, researchers now have been able to produce
different types off HPV16 vaccines, such as DNA vaccines, protein subunit
vaccines, virus-like particle (VLP) vaccines and recombinant live
vaccines. They were able to show that a genetically altered HPV16 L1
protein, a major capsid protein of HPV, can self-assemble into VLPs,
which can then induce a strong antibody response.

Therefore, the HPV16 L1 protein has been acknowledged as one of the best
candidates for the HPV16 prophylactic vaccine. Up to now, the HPV 16
protein has been produced mainly in yeast cells and genetically
engineered baculovirus-insect cells. However, these systems are too
expensive to be used for the generation of affordable prophylactic
vaccines for developing countries.

A Chinese research team, led by Dr. Si Lusheng from the Institute of
Cancer Research in the School of Life Science & Technology at Xi'an
Jiaotong University, has been interested in prophylactic HPV vaccine for
more than a decade. Now, they have been able to produce the human
papillomavirus type 16 L1 protein in genetically modified tobacco plants
for use as a possible vaccine.

Transgenic plants offer many potential advantages for the production of
therapeutics and vaccines: they are easily to use, simple, convenient and
inexpensive. Furthermore, the proteins produced by these plants can be
administered without giving them in the digestive tract. This is
especially important for HPV infections, because they are sexually
transmitted and only mucosal immunity route administration can provide an
effective vaccine for women.

Dr. Lusheng and his colleagues genetically engineered the tobacco plants
by cultivating them with Agrobacterium tumefaciens - a bacterium able to
transmit some parts of its genome in plant cells and therefore a widely
used tool - that harbored the HPV16 L1 gene. The researchers found, that
the HPV16 L1 gene was integrated stably into the genome of the tobacco
plants. Even more important, the tobacco leaves were able to produce the
HPV16 L1 protein, and the protein accounted for 0.034 to 0.076 percent of
the total soluble leaf proteins.

Dr. Lusheng also noticed that the protein formed virus-like particles as
large as 55 nm, which is compatible with HPV virus-like particles. When
Dr. Lusheng's team gave these particles to mice erythrocytes, they caused
the agglutination of the erythrocytes. Dr. Lusheng's laboratory also
demonstrated that, when anti-HPV16 L1 antibodies were added, they could
abolish the agglutination.

"The experiments confirm that the vaccine is able to invoke mucosal
immunity in the mucosa," Dr. Lusheng told Checkbiotech. And he continued,
"Since most of the HPV infections leading to cervical cancer would arise
through sex, a vaginal immunity induced by the vaccine would be very

However, there is a great barrier in HPV vaccine research - HPV cannot
infect any animals except humans, thus Dr. Lusheng and his team cannot do
any studies with animals to investigate the efficiency of the HPV vaccine.

"We hope the government will allow us to conduct clinical trials, and in
fact, the VLP vaccine is undergoing clinical trials in some other areas
of the world, and it has achieved some promising results," noted Dr. Lusheng.

There are some concerns that the oral administration of vaccines might
lead to tolerance rather than to immunity. However, it has been shown
that the oral tolerance could be prevented by using a mucosal adjuvant -
a chemical used to ensure a good immune response - such as LTB. It has
been shown that the oral delivery of HPV VLP induces a protective immune

The researchers suggest that the HPV16 L1 protein can be produced in
genetically engineered tobacco plants, and that these proteins are
identical to the natural HPV16 L1 proteins. Therefore, genetically
enhanced plants producing the HPV16 L1 could be used as an edible
vaccine. However, "as a plant HPV vaccine, the tobacco is not good," Dr.
Lusheng said.

Therefore, the researchers are now developing tomato chloroplast HPV
vaccines that will express large amounts of HPV proteins, which can be
eaten as an oral vaccine.

Due to the success of their initial research, Dr. Lusheng is now looking
forward to cooperating with the companies. With the right partner to help
him take his research to next level, he believes his research will lead
to a commercial product that would eliminate the risks of HPV induced cancers.

Katharina Schoebi is a biologist and a Science Writer for Checkbiotech.
Contact her at

Hong-Li Liu et al. Expression of Human Papillomavirus Type 16 L1 Protein
in Transgenic Tabacco Plants. Acta Biochimica et Biophysica Sinica. 37
(2005) p. 153-158

Si Lusheng
Insitute of Cancer Research
School of Life Science & Technology
Xi'an Jiaotong University
Xi'an 710061, China
Tel.: 86-29-82655191
Fax: 86-29-82655499

                                  PART II
-------------------------------- GENET-news -------------------------------

TITLE:  Crop biomanufacturing of enzyme gets underway in US
SOURCE: In-Pharma Technologist, France
DATE:   18 Jul 2005

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Crop biomanufacturing of enzyme gets underway in US

18/07/2005 - German biotechnology company ICON Genetics is to start field
trials of a transgenic tobacco crop that will be used to produce an
enzyme with potential as an active pharmaceutical ingredient and as a
catalyst for the manufacture of industrial chemicals.

The field trial, carried out in collaboration with the Kentucky Tobacco
Research and Development Centre (KTRDC) in Lexington, US, will involve
transgenic plants with genetically engineered chloroplasts containing a
phenylalanine ammonia lyase (PAL) gene from Arabidopsis thaliana.

An overexpression of the PAL gene in tobacco chloroplasts aims at both
pharmaceutical and industrial applications: the purified enzyme can serve
as a drug for the treatment of the inherited disease phenylketonuria
(PKU). The enzyme also serves as a biocatalyst for industrial biochemical
synthesis, particularly chiral compounds. Futhermore, expression of PAL
in the plants will lead to the accumulation of metabolites from the
phenylpropane pathway that are also of commercial value, according to Icon.

Making pharmaceuticals in crop plants such as tobacco is an attractive
proposition because they are inexpensive to grow, and could produce vast
quantities of drugs or vaccines at low cost, potentially making it
possible to make drugs that were not economically feasible before. But
moves in this area have been met with dismay by environmentalist groups,
alarmed that the GM traits could find their way into the food chain.

ICON said that biosafety aspects of the field trial, which has been
granted a release permit by the US Government's Animal and Plant Health
Inspection Service, have been 'carefully considered'.

The firm maintains that chloroplast-located transgenes generally do not
spread into the environment via pollen flow. Moreover, the genetically
engineered plants do not contain antibiotic resistance genes, according
to the company, since they were created using ICON's proprietary
resistance marker removal technology.

"The tobacco plants do not contain any foreign genetic sequences except
those required for PAL protein biosynthesis. Expression is achieved by
extending an existing operon, thus additional promoter elements, which
may lead to genetic instability, are not required," explained ICON's
manager, Christian Eibl.

                                  PART III
-------------------------------- GENET-news -------------------------------

TITLE:  Turning Over a New Leaf
        Md. Tests to Extract Tobacco's Proteins May Rescue Growers
SOURCE: Washington Post, USA, by Amit R. Paley
DATE:   17 Jul 2005

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read more about GE pharma tobacco at:
Participatory Assessment of Social and Economic Impacts of Biotechnology

Turning Over a New Leaf
Md. Tests to Extract Tobacco's Proteins May Rescue Growers

Five years after leaving the crop he spent his entire life growing,
fourth-generation tobacco farmer Steven Walter stepped into an Upper
Marlboro tobacco field on a recent sun-baked afternoon and cocked his
head in puzzlement. Everything looked terribly wrong.

Where there should have been neatly ordered rows, thick clumps of tobacco
knotted into an out-of-control, knee-high jungle. The leaves, which
farmers grow until the end of summer, had already been harvested. And
what were those glowing blobs of neon blue that coated the ground?

"It looks real strange to a tobacco farmer," said Walter, 44, of
Hughesville, as he squatted and touched a tobacco plant for the first
time since 2000. "But you can definitely still tell that it's tobacco."

The strange crop growing in this University of Maryland field is part of
an initiative that researchers believe will transform tobacco, which has
hastened the deaths of millions, into a plant with beneficial uses that
could enhance shampoos, treat kidney dialysis patients or even fight
certain types of cancer.

"It's the ultimate irony," said Gary V. Hodge, a creator of the project
and former executive director of the Tri-County Council for Southern
Maryland, a regional planning group. "But it might be just the thing that
ultimately keeps tobacco alive."

The federally funded initiative, known as the Alternative Uses of Tobacco
Project, is seen by some farmers as the only remaining opportunity to
revive a tobacco industry that was once the economic and cultural
backbone of Southern Maryland.

Six years ago, the Maryland General Assembly approved a first-in-the-
nation tobacco buyout. About 85 percent of the state's 1,000 or so
tobacco farmers -- Walter among them -- promised to stop growing tobacco
on their property in exchange for cash payouts.

But there was an exception: The land could be used to grow tobacco for
non-smoking "alternative" uses.

Now the U-Md. scientists are racing to complete their research before the
farmers, many of them senior citizens, die and the land is sold.

"All we need is a way for farmers to reengage in tobacco for a totally
different purpose than its historical purpose of smoking," Hodge said.

Although most of the tobacco fields have vanished, the crop's 400-year
grip on Southern Maryland remains strong. Charles County still crowns a
Queen Nicotina every year. The flag of neighboring Calvert County bears a
bright-green tobacco leaf. And anti-smoking newcomers to the area are
quickly reminded that tobacco fields were once as common as housing

"It was the money crop," said Pat Wathen, 69, president of the Charles
County Farm Bureau.

For more than a century, his family's La Plata farm grew up to 15 acres
of tobacco. But since he took the buyout and retired from farming, the
fields have been used only for personal use.

Other farmers have turned to different crops. Walter transformed his
tobacco operation into a 1,000-acre field filled with corn, soybeans and

"It's kind of a shame that whole way of life is dying out," Wathen said.
"It was definitely hard, labor-intensive work in hot, hot weather. But
you miss certain things."

In many ways, the experimental tobacco grown by U-Md. researchers at the
Upper Marlboro field bears little resemblance to the crop that Wathen
remembers. Traditionally, tobacco is grown in neatly ordered rows of
about 6,000 plants an acre and harvested yearly; the researchers hope to
grow up to 100,000 plants an acre, harvested four times a year. Instead
of placing each plant into the ground individually, they spray the seeds
on the dirt as part of a neon blue substance that glows in the sun.

When Walter grew tobacco, he spaced the plants out and tended every
harvested leaf with extraordinary care, hanging each one in a barn until
it was air-cured to perfection. But the scientists don't care about leaf
quality or taste. They care only about one thing: proteins.

"Proteins are used in everything from cosmetics to medicines," said Neil
A. Belson, a principal co-investigator on the project. "If we can grow
these proteins cheaply in plants instead of creating them in
multimillion-dollar reactors, there would be a real demand."

Belson said researchers are at least two years away from teaching
Southern Maryland farmers how to grow nontraditional tobacco. For now,
they are still experimenting with ways to extract the proteins from the plant.

Inside the project's processing facility, a building at the College Park
campus that once produced ice cream, researchers removed heaps of tobacco
from a walk-in refrigerator and demonstrated the extraction process to
Walter and several visitors.

"Ready to go!" Y. Martin Lo, an associate professor of food bioprocess
engineering, yelled to two assistants. They began dumping verdant tobacco
leaves onto a conveyor belt.

A green mist filled the air as the tobacco toppled into a machine that
pulverized the leaf. The entire room smelled of freshly cut grass.

The researchers then fed the pulp into a device that began to squeeze the
protein-filled juice into a bucket. An excited Belson peered into the

"You're seeing the future of tobacco!" Belson exclaimed as he turned to

The farmer didn't seem quite convinced. "I think we've still got to wait
and see how this works," he said.

Although farmers in Maryland are waiting to see if the U-Md. project pans
out, biotechnology experts say tobacco is one of the plants most likely
to produce beneficial drugs in the near future. Since 1999, the U.S.
Department of Agriculture has received 15 permit applications from
companies seeking to grow genetically modified tobacco to produce
pharmaceuticals. Some companies have already conducted trials on anthrax
vaccines and anti-cavity drugs grown in the plant.

"There is no doubt in my mind, absolutely no doubt in my mind, that in
the not-too-distant future -- certainly our lifetimes -- we will see
biomedical compounds derived from tobacco plants," said Val Giddings,
vice president for food and agriculture of the D.C.-based Biotechnology
Industry Organization.

But even proponents concede that it will take years and hundreds of
millions of dollars before some of the tobacco-based drugs reach the
public. Many may never make it to market.

Giddings cautioned that the genetically engineered tobacco would not
require nearly as many growers as did the traditional crop.

As Walters stood and gazed at the research field, with a traditional red-
roofed tobacco barn aging in the distance, he said most younger farmers
would want to try the nontraditional tobacco -- if it is profitable.

"Nostalgia is all well and good for newcomers and politicians," he said.
"But farmers are only going to grow tobacco again if we can make money on it."


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