(TOXIC) GM Pharmaceuticals from Common Green Alga

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GM Pha.rmaceuticals from Common Green Alga

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GM Pharmaceuticals from Common Green Alga

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Amid widespread protests against using crop plants to

produce genetically modified pharmaceuticals, companies are

turning to the single-cell green alga Chlamydomonas touted

as a " safe " alternative; but not when it is to be grown in

largescale outdoor bioreactors Prof. Joe Cummins and Dr.

Mae-Wan Ho

 

A fully referenced version of this article is posted on ISIS

members' website http://www.i-sis.org.uk/full/PICGA.php.

Details here http://www.i-sis.org.uk/membership.php

 

Largescale production of GM algae producing human proteins

 

The Hawaii Department of Agriculture received an application

from Mera Pharmaceuticals, originally filed 1 November 2004,

for a permit to begin large-scale production of a

genetically modified (GM) alga, Chlamydomonas reinhardtii,

producing a human immunoglobulin-A protein against a variant

of the herpes simplex virus. On 17 April 2005, Mera

Pharmaceuticals revised their application to include seven

additional GM strains expressing a range of human

antibodies, interleukins and nerve growth factors (see Box)

[1]. The case for the first GM strain was heard on 25 May

2005, and the Plant Quarantine Honolulu Office did not grant

the permit.

 

The application for the seven other GM strains had been

scheduled for 7 October 2005, but was brought forward to 29

June. On that occasion, the state Board of Agriculture gave

its approval [2]. Mera Pharmaceuticals will begin the

process of importing the microalgae from The Scripps

Institute, La Jolla, California, even as opponents are

seeking to block the permit, which was approved on a six-to-

two vote after nearly three hours of testimony and an hour

of discussion.

 

Single cell green algae are serving as green cell factories

for producing pharmaceuticals, and have been touted as a

safe alternative to producing them in crop plants, because

they can be contained in the laboratory [3, 4].

Unfortunately, Mera's proposed large-scale cultivation is

not contained. Anything from 500 to 26 000 litres of culture

are housed in transparent " Outdoor Photobioreactors " , which

are cooled with cold seawater with added chlorine [1]. The

exposed facilities are prone to weather, storm and other

damages, resulting in immediate massive contamination of the

marine environment. In addition, the use of chlorinated

seawater for cooling will be expected to impact on marine

life. Neither of these concerns appeared to have been

addressed. Henry Curtis, executive director of Life of the

Island, told the Board that the nonprofit organization will

file for a contested case hearing.

____

 

GM Chlamydomonas strains to be imported into large-scale

culture facility in Hawaii

 

1. Strain Hsv8, producing a full-length human

immunoglobulin-A against a variant of the herpes simplex

virus

 

2. Strain aFceR 1r-1, producing a protein targeting the Fc

portion of the IgE molecule, thereby limiting the

interaction between circulating IgE molecules and receptors

on mast cells, which is turn limits the release of

histamines and reduces inflammation.

 

3. Strain aTNFr-1, producing IgG1 anti-tumor necrosis factor

antibody.

 

4. Strain a TNr-1, producing IgG1 anti-microbial antibody.

 

5. Strain aCRr-1, producing IgG1d anti-cell proliferation

antibody.

 

6. Strain aBSSsr-1, producing anti-cancer cell specific

antibody.

 

7. Strain aIL 10r-1, producing various interleukins

(including interleukin 10, interleukin 13. interleukin 5 and

interleukin 3)

 

8. Strain aARTr-1, producing neurotrophic factors to

stimulate the growth of new nerve tissue.

 

____

 

The GM algae will be imported into Kona on the island of

Hawaii to be grown in the outdoor bioreactor system at

Keahole Point at the state's aquaculture park Nelha. As

Nancy Redfeather, Director of Hawaii Genetic Engineering

Action Network (Hawaii GEAN ) points out, this type of

" field trial " of a biopharmaceutical algae has never been

attempted before in the United States, and all government

agencies, the Food and Drug Administration (FDA), the US

Department of Agriculture (USDA) and Environment Protection

Agency (EPA) had waived oversight of the trial. The native

Hawaii algal systems have not been well documented; nor has

the ecology of Chlamydomonas itself. Apart from some last

minute attempt to conduct basic environmental experiments of

the survival of GM algae, there are no peer-review studies,

or studies of any kind to back up Mera Pharmaceutical's

claim of " no harm to the environment or human health. "

 

Written and oral testimony by the public was overwhelmingly

opposed to the project. The board also ignored testimony and

reports by a number of local algae experts from the

University of Hawaii, Manoa, the State Biologist and Maui

Country District Health Officer. Other scientists providing

testimony include R. Malcolm Brown Jr., the Johnson and

Johnson Centennial Chair in Plant Cell Biology at the

University of Texas at Austin; Marti Crouch, Doug Sherman

from Friends of the Earth, and Joe Cummins and Mae-Wan Ho

from ISIS.

 

Malcolm Brown's message to the board was, " Hawaii is still

the supreme ecosystem on earth to understand the dynamics of

evolution and natural selection. Let's not forever lose this

opportunity because a few commercial operations

thoughtlessly tried to construct mass scaleup of genetically

modified organisms in Hawaii. "

 

Nancy Redfeather said, " It was indeed a sad day for the

native algae of Hawaii island.

 

The Chlamydomonas reinhardtii transformation

 

Chlamydomonas reinhardtii is a preferred organism for

molecular pharming by chloroplast transformation because its

nuclear and chloroplast genomes have both been sequenced,

and it has a long history of laboratory culture. In

addition, it has a single chloroplast, which makes it easy

to produce a uniformly transformed culture. One technical

drawback with the alga is codon bias related to the high GC

content of the algal DNA, To achieve significant production,

the code of human and many other genes must be altered to

fit the bias of the algal cell, For that reason the human

pharmaceutical products are produced from synthetic

approximations of the human gene [5]. The synthetic human

DNA in the alga, and all the more so, the expressed

transgene, should not be deemed equivalent to the human gene

and gene product until they have been tested for untoward

effects on humans and other organisms in the environment. It

is already known that the proteins are not subject to post-

translational modifications [3] as they would be in human

cells, and hence likely to be treated as `foreign' by the

human immune system.

 

Mayfield and Franklin described construction of transgenic

Chlamydomonas reinhardtii whose chloroplasts had been

modified to express human antibodies [6]. The human genes

were extensively adjusted for codon bias. Either the rbcl

(ribulose-1,5-bisphosphate carboxylase of the chloroplast)

promoter or the atpA (alpha-subunit of the chloroplast ATP

synthase of the chloroplast) promoter were used to drive the

antibody gene, with the rbcL transcription terminator

following the human gene. A 16S ribosomal subunit with

resistance to the antibiotic accompanied the human gene

transformation. Using this system, IgA antibody directed

against herpes simplex virus were produced [6], as well as

single chain antibodies against the herpes virus [3]. The

numerous codon alterations to optimize production of

recombinant protein in the alga have been described [7].

Code optimization need not change the amino acid sequence of

the protein produced from the recombinant gene, but Mera's

petition contained no proof that the protein produced from

the synthetic gene was identical to the original human gene,

nor the fact that the transgenes were synthetic

approximations to the human genes.

 

Although not prominently stated, the GM strains probably all

contained in addition a kanamycin resistance marker gene

[1], which is necessary to select for the transformed cells.

 

Risks from the GM alga

 

The claim that the risk from contact with the recombinant

products was negligible even in the worst case is

groundless, because no experiments were reported to support

that conclusion.

 

As pointed out already ( " Molecular pharming by chloroplast

transformation " , this series), producing pharmaceuticals in

chloroplasts entails specific risks due to the large

quantities of transgenic proteins produced and the hazards

of horizontal gene transfer to bacteria due to homologies

between the chloroplast and bacterial genomes.

 

Large quantities of transgenic proteins are produced from

multiple copies of transgenes present, in the case of

Chlamydomonas, about 50 to 100 per cell. Strains 2-6 (see

Box) produce antibodies that bind to immunologically active

proteins that could lead to anaphylaxis (severe life-

threatening allergic reaction) following repeated exposure.

Strain 7 produce interleukins, potent regulators of immune

functions active in minute quantities. Pulmonary exposure to

interleukin 13, for example, causes inflammation, mucus

hypersecretion, physiologic abnormalities associated with

asthma [8], while interleukin 10 is a powerful immune

suppressant [9]. Strain 8 produces unspecified neurotrophic

factors to stimulate growth of nerve tissue, again, potent

molecules active at very low concentrations, whose effects,

especially at high concentrations are completely unknown.

 

An additional hazard from the gene products is that they are

in all cases not the same as the human protein, because of

the changes in making the synthetic gene copies, and because

there is no post-translational processing. They may hence be

treated as immunologically `foreign' by the human immune

system, resulting in dangerous complications.

 

Horizontal transfer of the GM Chlamydomonas transgenes are

likely to occur in all environments, particularly in the

soil, where Chlamydomonas is commonly found, but also in the

marine environment and in the gastrointestinal tract of all

animals. Horizontal transfer of transgenes can occur both

from the accidental release of genetically modified

Chlamydomonas reinhardtii itself, or from the intentional

release of transgenic DNA in the large amounts of transgenic

wastes that are likely to be discharged from the large scale

culture facilities into the environment.

 

As already mentioned, horizontal transfer and recombination

of transgenes could create new bacteria and viruses that

cause diseases and spread antibiotic resistance marker genes

to the pathogens

 

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