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We thought initially the ATRYN market in Europe is just 'proof of concept' but it obviously has balooned to a lucrative proposition especially on the pricing side.
So why GTCB & LEO have not issued any kind of PR yet ? And we have to find the info. thru some articles...
What are they waiting for ?
If we don't find any insider buying at these levels, when will we ?
However the better side of me tells me something may be atworks...the street drives down the stock only to load up more pending news around the corner.
Hope we get some insider buying tomorrow..
The way the stock is behaving post 3Q CC, I am seriously beginning to doubt on any deals at all. GTCB is minimum 2 years away from generating any viable revenue and they don't have funds beyond 2 half of 08.
Any big pharma if they were interested would have jumped on GTCB's transgenic patents value alone. Also none of the analysts have issued any buliish calls especially after recent CC, if indeed any short term drivers are on the horizon.
No news on Europian reimbursement rates either....
Just curiouis (ok, dying to know)...that single analyst who asks couple of standard questions in every GTCB quarterly CC calls takes notes ok...then what ? No recom, no other report..!!
He seemed to praise the milestones reached during the recent call and I was hopeful, he will issue some ratings on the stock but just silence..
Well, 4Q here it comes with good top line results before then hopefully..
Could deal with Bayer possible ? After all they (Bayer) were close to partnering with PPL Therapeutics (now defunct) but that was long time back.
Exactly ! Traced the demise of PPL and saw a piece of that company landing up in Pittsburgh backyard and Pharma group gobbling up the Patent portion.
I am curious to know why Bayer pulled out of the investment though.
Message: 5088 ---> My apology for posting old article...it had the date of 25 sep 2007 at the top and I assumed the article is current. Later I found the article to be from a past issue..
25 September 2007
Uncorking the biomanufacturing bottleneck
from Nature Biotechnology
Alan Dove
As biomanufacturing capacity becomes strained, several new methods for producing biologics are being investigated by biotechnology companies.
The future for biologics manufacture? Sheep being milked at the dairy of PPL Therapeutics' pilot production plant in Scotland.
© PPL Therapeutics
Molecules produced by organisms or cultured cells—so-called biologics or biopharmaceuticals—are currently the mainstay products of the biotechnology industry. Biologics, which include protein hormones, engineered protein-based vaccines, and monoclonal antibodies, can precisely modify a patient's physiology, often with greater success and fewer side effects than traditional small-molecule drugs or vaccines. Indeed, early biologics—Amgen's (Thousand Oaks, CA) recombinant erythropoietin and Genentech's (S. San Francisco, CA) human growth hormone somatropin—have proven that these drugs can benefit huge numbers of patients and generate handsome profits. But biologics are fast becoming victims of their own success, and a looming deficit in biomanufacturing capacity threatens to restrict the expansion of the commercialization of this group of products.
The manufacturing crunch
In 1998, Immunex (Seattle, WA) launched Enbrel, a soluble tumor necrosis factor (TNF) receptor used to treat rheumatoid arthritis. Demand for the drug rapidly outstripped its supply, forcing the company to make large capital investments in the construction of new production facilities while scrambling for partnerships with companies that might provide additional capacity. When the smoke cleared, Amgen had announced it would acquire Immunex, and Enbrel was monopolizing the worldwide capacity for biologics manufacturing.
Although Immunex has become the poster child for the biomanufacturing bottleneck, experts suggest that the Enbrel story is only the beginning. "There are ten antibodies on the market today, and they're essentially consuming all the [manufacturing] capacity that's available. There may be as many as 500 more in development," according to Tom Newberry, a spokesman for GTC Biotherapeutics (Framingham, MA; previously Genzyme Transgenics). Newberry foresees 20 new monoclonal antibodies reaching the drug market in the next ten years, necessitating a 200% increase in manufacturing capacity for that class of proteins alone. This estimate may even be a conservative one: many biologics are being developed to treat chronic conditions, and proteins, which tend to be broken down in the bloodstream, often have to be given in larger doses than small-molecule drugs.
The current standard technology in biomanufacturing, which uses cultured Chinese hamster ovary (CHO) cells in bioreactors, presents major difficulties for companies seeking to scale up. Because nutrients, heat, and gases must diffuse evenly to all cultured cells, the laws of physics set strict limits on the size of bioreactors. Building more bioreactors multiplies costs linearly. A CHO cell–based biomanufacturing plant can cost upwards of $250 million, and an error in estimating demand for, or inaccurately predicting the approval of, a new drug can be incredibly costly. To compound the problem, regulators in the United States and Europe demand that drugs be produced for the market in the same system used to produce them for the final round of clinical trials, so companies have to build facilities for drugs that might not be approved.
Pursuing a wide range of methods, several companies are now developing new technologies to address this capacity crunch. These include biomanufacturing in domestic mammals, chickens, and plants (see Table 1).
Proteins by the herd
Both GTC Biotherapeutics and PPL Therapeutics (Edinburgh, United Kingdom) have developed herds of transgenic animals that express therapeutic proteins in their milk. April D'Arcy, a spokesperson for PPL, says: "The actual synthesis phase occurs within the animal, under the control of the animal's own physiology. This is clearly an advantage over, for example, cell culture, where the culture conditions themselves have to be controlled within very tight limits."
The mammary "bioreactor" also has the advantage of having evolved for the sole purpose of secreting proteins. "We're dealing with cells that are specifically designed to secrete proteins in a much more packed density. As a result we're able to get much more complex proteins than a standard bioreactor is typically able to get to," says Newberry. As biotechnology research yields greater insights into disease, the ability to manufacture more complex biologics may give transgenic animals a distinct advantage over other biomanufacturing techniques.
There are still bumps ahead for the technology. For example, goat breeding has a turnaround time of approximately 18 months. And some therapeutic human proteins could be detrimental to animals' health when expressed in their mammary glands.
Even with these caveats, animal-based systems have significant advantages over traditional bioreactors in scalability and financial risk. Newberry estimates that a company can get GTC Biotherapeutics to produce a transgenic goat for about a tenth of the cost of that required to build a traditional biomanufacturing facility. If a biologic produced in transgenic animals is successful in clinical trials, a company can enjoy agricultural economies of scale instead of linearly increasing building costs, as traditional breeding can cheaply enlarge the herd.
Or the flock: AviGenics (Athens, GA) is one of several companies working with transgenic chickens (see Table 1), the eggs of which are easily harvested, natural protein-producing systems. Tony Cruz, AviGenics' vice president for corporate development, contends that chickens have a distinct advantage over goats and other dairy animals, as it "takes an egg 21 days or so to hatch after a hen lays it, and a chick will take in the neighborhood of six months to be able to generate her own eggs or reproduce, so you have a very quick turnover." The company has successfully introduced transgenes into chickens using a retroviral system (Nat. Biotechnol. 20, 396 – 400, 2002) and is now developing nonretroviral transgene systems.
According to AviGenics' estimates, a flock of 4,000 hens could produce approximately 100 kg of a biologic drug per year, and each hen occupies about one square foot of space in a chicken coop. "If you want to increase your protein production, it's not a matter of building a new plant, it's a matter of building a new chicken house," says Cruz.
Although chickens may ultimately give goats a run for their money, the production of transgenic birds is still several years behind transgenic mammal technology. "At this stage of the game we are still being looked at as an alternative system," says Cruz, as "anyone who's looking for a biomanufacturing system can't put all their eggs in one basket."
Green proteins
The ease of genetically modifying plants has inspired a few companies to seek bioreactors even earlier in the food chain, a strategy that could eventually produce even greater cost savings (see Table 1).
ProdiGene (College Station, TX), for example, has developed an expression system that produces a desired protein in the kernels of corn, the part of the plant traditionally harvested for food. Zivko Nikolov, vice president for process development and production at ProdiGene says: "Downstream processing is fairly simple. We have a fairly good idea of how to extract the corn kernel and to maximize the efficiency of corn processing." As an added benefit, proteins expressed in the kernel are not degraded the way they would be if expressed in stems or leaves.
Depending on the plant, scaling up production could be even faster than it is for chicken-based systems, as a single progenitor plant can produce thousands of seeds after a few months of growth in a greenhouse.
Besides being cheap to grow and propagate, plants offer an additional benefit over animal systems. "With animals ... one of the most distinguishing issues is safety with respect to agents such as viruses and prions," says David Williams, chief technology officer of CropTech (Blacksburg, VA).
GTC Biotherapeutics's Newberry concedes that "any bug that infects a plant doesn't infect a person," but adds that "the obverse of that is that if the wind blows through my barn, I'm not going to get a goat pregnant on the other side of the fence. I don't have a problem with genetic material going someplace I don't want it to go."
Indeed, a major challenge for would-be plant biomanufacturers has been to develop containment procedures to ensure that neighboring food crops will not start expressing prescription drugs.
Williams cites this as an advantage of CropTech's system, in which therapeutic proteins are expressed in tobacco leaves. "Once we're in the field, we don't let the plants go to the flowering stage and the point where they actually produce pollen." Even in the event of cross-contamination, "we're about the only plant system out there right now that is a non-food and non-feed crop."
However, field trials of biologic-producing crops will require strict containment procedures. ProdiGene, which plans to use corn to produce trypsin for the biomedical research market, has obtained US Department of Agriculture (USDA; Washington, DC) approval for the first large-scale commercial production of a recombinant protein in plants. In addition to being spatially isolated from nearby cornfields, the company's 400 acres of transgenic corn will be "temporally isolated" by being planted at least 21 days earlier or 21 days later than the surrounding corn, to ensure that the fields are not producing flowers at the same time. Under recent USDA regulations, the field must also be planted and harvested with equipment dedicated to the genetically modified crop. If the trypsin field trial is successful, ProdiGene plans to use the system to develop its own pipeline of biologic vaccines and other products.
Perfecting proteins
One problem that is likely to affect all biomanufacturing systems to varying degrees is the difficulty of producing proteins in their most active form. Proteins must not only be folded correctly, but also be properly glycosylated—they must have specific sugar structures attached at the correct sites on the molecule in order to be maximally effective (Nat. Biotechnol. 19, 913 – 917, 2001). Mammalian systems like transgenic goats may yield near-human patterns of protein glycosylation, and some preliminary evidence suggests that avian systems may do even better, but it remains unclear whether "close enough" will be good enough for the manufacture of biologic drugs.
To address this problem, Neose (Horsham, PA) is developing a system that can be used to glycosylate proteins derived from any biomanufacturing process. The company's general strategy is to use glycosylation enzymes to modify a protein's sugar residues in a test tube, either to make the protein bear a closer resemblance to the native protein, or to introduce chemical modifications that nature never intended.
"One area we're focusing on is completely remodeling high-mannose chains, which are put on by yeast," says David Zopf, executive vice president of Neose. When proteins are manufactured in yeast and then introduced into humans, the high-mannose sugar groups cause the proteins to be cleared rapidly from the bloodstream, drastically reducing their half-life. If Neose can remove or modify these structures, many biologic therapies might be produced cheaply in large yeast-fermentation vats—one of the oldest drug-manufacturing systems.
In addition to helping other companies produce their own biologics, Neose is pursuing a second strategy that suggests broader business opportunities for biomanufacturing companies. "We're realizing that there's an opportunity for us to go back and apply some of these modern technologies to compounds that have been around for awhile, some of them coming off patent," says Zopf. By reducing the production costs and improving the pharmacodynamic profiles of off-patent biologics with known efficacy, biomanufacturing technology companies might be able to develop their own drug pipelines with relatively little risk.
Although Neose seeks to solve the glycosylation problem, other biomanufacturing companies hope simply to ignore it. According to CropTech's analysis, "about 70% of the total monoclonal antibodies in the pipelines [of biotechnology companies] we are absolutely sure don't require glycosylation," says Williams. To produce proteins for which glycosylation is critical, manufacturers might prefer nonplant systems.
Despite the companies' diverse strategies, experts in biomanufacturing seem to agree that no single technology will dominate the field. As CropTech's Williams says, "There is no perfect system out there, but...if you look at the predicted statistics on pipeline molecules, there's a lot of business for different manufacturing technologies out there." GTC Biotherapeutics's Newberry agrees, adding; "In the end I think there's a reasonably good likelihood that everybody [in biomanufacturing] can succeed."
Dew, after listening to the presentation to Think Equity on Tuesday, I am wondering why there was no mention about potential partnership for the Atryn US market.
I was expecting atleast a mention that GTCB is engaged in some level of discussions with the potential partners.
After that, GTCB becomes a trading stock as opposed to a value stock
This comment may very well be not the first time..I am sure someone said the same thing when CELG was in that range before the 3 splits and the current price of $65
I agree. That's why marked improvement in DIC scores before and after is very important in the trial.
As Dew pointed out earlier, improvement in DIC scores should correlate to survival benefits (atleast in DIC patients).
The more I read these #'s off of pre-clinical trials of AT in DIC indications, I cannot help but realize the Leo's PII trail got to be successful.
"In a more recent study where 35 patients with DIC associated with severe sepsis received high doses of AT versus placebo, a 44% reduction in mortality was shown in the AT group8.
In a recent retrospective analysis of the KyberSept trial in patients with sepsis and DIC, a clear reduction of 28 and 90 days mortality was shown within patients with DIC as compared to patients without DIC. At 28 days, there was 25.4% mortality among the patients treated with antithrombin compared to 40% mortality for those patients that received a placebo. At 90 days, there was 34.3% mortality among antithrombin treated patients compared to 50.4% mortality among patients treated with a placebo "
Dew,
Per information posted on the govt. clinical trial site,
http://www.clinicaltrials.gov/ct/show/NCT00506519;jsessionid=A2E3DEF0A70B56B59173DF6D7219AAC9?order=...
Further study details as provided by LEO Pharma:
Primary Outcome Measures:
Patients alive on day 28 having had an improvement in DIC score and having had no worsening on organ failure score.
Secondary Outcome Measures:
Mortality at 28 and 90 days. Change in organ failure score and DIC score. Pharmacokinetic (PK) parameters.
The Primary Outcome clearly says the Patients need to be alive on Day 28 while only improvement is needed in DIC score.
Is this not considered as Survival benefit (that needs to be met) ?
TIA
Thanks for the clarification.
CONCLUSIONS: Mortality was reduced by 44 percent in this trial, but the difference did not reach the statistical significance. Circulating protein C and protein S levels were not modified by ATIII supplementation. High doses of ATIII concentrates significantly improved sepsis-induced DIC during septic shock. The trend toward improved survival suggests further randomized studies.
Is 44% not statistically significant ??? Am I missing something here ?
This is from Q1 2006 CC transcript..which should clear any misgivings related to immmunogenicity issues.
On the issue of immunogenicity, I have stated many times that we have not seen any anaphylactic or allergic responses in any of the over 200 patients who have been treated with ATryn® in a number of clinical studies, including those patients given multiple doses. Nor have we identified antibody response to goat proteins or goat antithrombin nor inhibiting antibodies to ATryn®, and we have looked intensively for evidence of these.
We have argued the immunogenicity issue strongly in our response. Remember that the total potential level of contaminating proteins that may be present is 5 parts per million, or to say it another way, ATryn® is 99.9995% pure. This is a remarkably pure product, and as such, we believe carries a low inherent risk for immunological concerns from contaminated proteins
No antibodies to ATryn have been observed in any of the several hundred subjects who have received ATryn during the past decade.
Dew...this statement has awesome implication for lot of naysayers in science of transgenics.
Heck...your statement made me feel so good, just added 5k more..
OT...on the unlucky side, remainds me of Nuvello..
Lost a ton of money due to overhype by both Nuvello's management and the street firms...again few in the inside did know about the stink bomb (heavy option trading)..
I distinctly remember, Dew showed some Nuvello P3 protocol details with FDA that had no margin of error which on a hindsight was a red flag that screwed scores of investors..
Dew, I agree with your optimism. It was particularly interesting to hear the upbeat presentation by Dr Cox & others during the recent CC.
One doesn't casually use the words 'update the progress' unless something is in the works.
During the recent CC call, Dr. Cox did mention being frustrated with PPS. But I fail to understand why they are not doing dog & pony show at the street. A well thought out road show will only attract a commercial partner with deep pockets.
That remainds me of Nuvello partnership with Bayer.,.. of course, both of them bit the dust which is a different story.
The nearest catalyst for GTCB is rates for reimbursement in EU countries which might give better insight into revenues down the road.
The analysts particpation is likely to more once the top line results are announced for P3 Atryn for US market end of this year...unless of course they sign up a commercial partner before then and we would then see the fireworks in the 3Q CC
After listening to COX presentation earlier, just bought more...Based on US market potential for Atryn alone with gross margin (~50%) for GTCB will make the PPS on the stock north of $10 easily...
10 bagger for sure in a year
I am not worried a bit about cash flow. The top line results on Atryn P3 in US would be good enough to get the BLA approval.
I bet a commercial partnership in US will not be far off by then and milestone payments will start to kick in..
All, IMHO
I for one will be listening more to the Q&A sessions especially Q from the analysts. Hope the participation is lot more this time.
This CC could be the start of the street noticing our little gem.
I 100% agree with GTCB being 'future' CELG from PPS & timeline standpoint. Actually may do much better than that considering outstanding on CELG is approx. 3 times that of GTCB. And CELG is at $60 bucks a share !!
Looking at the pre-clinical trial results for use of Atryn in DIC indication (where the money is) I think we have a winner.
Clinical trials with antithrombin in the treatment of patients with DIC associated with severe sepsis
In controlled trials with AT versus heparin or placebo, AT concentrate has proven superior to the control treatment with regard to shortening the duration of symptoms of DIC or reducing mortality in patients with shock and DIC. In a study with 51 patients with shock and DIC, three treatment groups were studied: AT, AT + heparin and heparin. AT-treated patients had quicker resolution of DIC symptoms; patients treated with AT + heparin had increased bleedings and no additional benefits (7).
In 133 patients with septic shock and DIC, AT was compared to a control group on heparin. The overall mortality was 14% in the AT group vs. 30% in heparin group; in the sicker patients the difference in mortality was even more striking (31% AT vs. 89% heparin) (9).
In a more recent study where 35 patients with DIC associated with severe sepsis received high doses of AT versus placebo, a 44% reduction in mortality was shown in the AT group (8).
In a recent retrospective analysis of the KyberSept trial in patients with sepsis and DIC (13), a clear reduction of 28 and 90 days mortality was shown within patients with DIC as compared to patients without DIC, as shown in the Table 1 below.
Based on the normally accepted Price to Sales ratio valuation model, could GTCB fetch north of $5 pps in 2008 or beyond ?
If we take the reasonable ratio for such companies to be 1 (PSR = 1), GTCB need to book 0.5 billion dollars (12 months trailing) to have PPS of $5. And assuming 0 long term debt.
I used the formula (PSR = ((Total common * PPS) + debt))/Sales)
Artisan Pharma might be ahead of GTCB on DIC indications where the real revenue is....
Safety and Efficacy of ART-123 in Subjects With Sepsis and Disseminated Intravascular Coagulation
This study is not yet open for patient recruitment.
Verified by Artisan Pharma, Inc. June 2007
Sponsored by: Artisan Pharma, Inc.
Information provided by: Artisan Pharma, Inc.
ClinicalTrials.gov Identifier: NCT00487656
Purpose
The purpose of this study is to see if ART-123 (recombinant human soluble thrombomodulin) decreases the number of people who die as a result of Disseminated Intravascular Coagulation (DIC) complication of sepsis.
Condition Intervention Phase
Sepsis
Disseminated Intravascular Coagulation
Drug: ART-123 (recombinant human soluble thrombomodulin)
Phase II
MedlinePlus related topics: Bleeding Disorders; Blood and Blood Disorders; Sepsis
Genetics Home Reference related topics: Bleeding Disorders; Blood and Blood Disorders
Study Type: Interventional
Study Design: Treatment, Randomized, Double-Blind, Placebo Control, Parallel Assignment
Number of arms in study: 2
Official Title: A Randomized, Double-Blind, Placebo-Controlled, Phase-2B Study to Assess the Safety and Efficacy Effects of ART-123 on Subjects With Sepsis and Disseminated Intravascular Coagulation
Further study details as provided by Artisan Pharma, Inc.:
Primary Outcome Measures:
One explanation is somebody is buying and selling in his own account (or between two accounts). All he will loose few bucks on roundtrip but can make it appear that the stock is trading higher.
Immune Reactions to Transgenic Protein Serious
Independent Scientists Demand A Ban on GM Food & Feed while All GM Crops Are Tested
The following memo and report were sent to international and national regulators on behalf of the Independent Science Panel.
Please circulate widely, forward to your regulators and policy makers, and the press.
From: Dr. Mae-Wan Ho, member of Independent Science Panel ( www.indsp.org ),
Director, Institute of Science in Society ( www.i-sis.org.uk )
To: (see list at the end)
I am writing on behalf of the Independent Science Panel (ISP)* to draw your attention to new research findings on the safety of transgenic proteins that need to be urgently addressed.
Specifically, immunological assessments carried out for the first time on a transgenic protein revealed that post-translational processing subsequent to gene transfer into an alien species introduced new antigenicities that turned a previously harmless protein into a strong immunogen. In addition, the transgenic protein promoted immune reactions against multiple other proteins in the diet. The detailed findings are reviewed in the report below.
As practically all the transgenic proteins involve cross-species gene transfer, they will be subjected to different post-translational processing, and hence they too, will have the potential to become immunogenic. And yet, none of the transgenic proteins that have been commercially approved has been tested. This omission is a most serious public health issue.
We call on you to impose an immediate ban on all GM food and feed until proper assessment on the immunogenicity of all the transgenic proteins has been carried out.
*The ISP, launched 10 May 2003 at a public conference in London, UK, consists of dozens of prominent scientists from 11 countries spanning the disciplines of agroecology, agronomy, biomathematics, botany, chemical medicine, ecology, epidemiology, histopathology, microbial ecology, molecular genetics, nutritional biochemistry, physiology, toxicology and virology
( http://www.indsp.org/ISPMembers.php )
Transgenic Pea that Made Mice Ill
Raises serious safety concerns on transgenic proteins in general that must be addressed while a ban on all GM food and feed is imposed
Dr. Mae-Wan Ho
Ten-year project down the drain but are the right lessons learned?
A ten-year project at CSIRO (Commonwealth Scientific and Industrial Research Organization) in Canberra Australia bit the dust when peas modified to resist insects caused inflammation in the lungs of mice [1]. The GM peas will be destroyed, said Gene Technology Regulator Sue Meeks.
The gene coding for the protein, a -amylase inhibitor-1 ( a A1) in the common bean ( Phaseolus vulgaris L. cv. Tendergreen), was inserted into pea ( Pisum sativum L.) to make the pea-plants resistant to attack from weevils.
Dr. T.J. Higgins, deputy chief of CSIRO Plant Industry and co-author of the scientific paper reporting the results remarked it is only the second time in the world that a GM project has been abandoned after a gene transfer from one crop to another, and that it demonstrated the effectiveness of strict regulations on research into GM crops.
Greenpeace campaigner Jeremy Tager said: “It just shows the failure of the science in relation to this gene product.”
Director of GeneEthics Network Bob Phelps referred to the project as a “waste of public money” and highlights the growing concern worldwide about the health impacts of all GM foods.
There are indeed important lessons to be learned from the scientific findings [2], which raise serious safety concerns over transgenic proteins in general.
Different processing of transgenic protein
The researchers found that the transgenic protein was processed differently and provoked immune reactions not exhibited by the native protein (see later).
Transgenic a A1 protein was compared with the non-transgenic protein on Western blot, a technique that separates different forms of the protein arising from post-translational processing. Previous studies showed that the native polypeptide in bean is cleaved into two chains, a and b , both of which are glycosylated (carbohydrate chains added), and with one or more amino acids removed from the tail end. This results in major forms of the a- and b- chains with molecular masses 11 646 Da and 17 319 Da respectively, together with minor forms containing alternative carbohydrate chains. The transgene in pea yielded a- and b -chains with molecular masses in the11 000 – 18 000 Da region, but with a banding pattern different from the native protein. More detailed comparisons on mass spectroscopy showed that the transgenic a -chain was less heavily glycosylated; and a form with two fewer mannose residues (11 322 Da) was the dominant in transgenic pea, but the least abundant in bean. The b -chain in the transgenic protein also showed a number of other bands besides the major and minor forms present in the native protein.
Immune reactions to transgenic protein
Mice were given about 25mg of seed meal in suspension, containing transgenic pea, nontransgenic pea, or bean, twice a week for 4 weeks. Seven days after the final feeding, the mice were subcutaneously injected in the footpad with the purified protein antigens: native or transgenic a A1, and the swelling induced in the footpad assessed 24 h later.
In a second experiment, the mice were fed seed meal suspensions as before, and seven and nine days after the final meal, purified transgenic a A1 or buffered saline was introduced into the trachea, and inflammation response was measured in the lungs 24 h later.
The results showed that mice fed on non-transgenic pea or bean showed no inflammation response in the footpad or in the lungs, indicating normal immune tolerance to common food.
Mice fed with transgenic pea, however, showed a A1-specific IgG antibodies at two weeks, rising to significant levels after 4 weeks. There was significant swelling of the footpad, or delayed type hypersensitive (DTH) response, when purified a A1 was injected. Similarly, introducing the antigens into the trachea gave an inflammation response in the lungs.
As a control for the general effect of genetic modification, the footpad challenge experiment was repeated with material from two other GM plants, lupin expressing sunflower seed albumin (SSA) and chickpeas expressing a A1. In contrast to transgenic pea, mice fed transgenic lupin or transgenic chickpea did not give DTH response. This shows that the response to transgenic pea was specific.
The peribronchial lymph nodes of the mice were tested for their response to transgenic a A1. Only the lymph nodes of mice fed transgenic peas responded by producing the inflammation cytokines (cell signalling factors) when challenged with transgenic a A1.
Transgenic protein promotes reactions to other proteins
In order to test if the transgenic protein promotes immune reactions to other proteins in the diet, mice were fed purified transgenic or native a A1, or transgenic a A1 with or without ovalbumin three times a week for 2 weeks. One week following feeding, purified ovalbumin or buffered saline were introduced into the trachea of the mice, and inflammation response in the lungs was assessed as before.
Neither ovalbumin alone, nor ovalbumin in combination with native a A1 caused any inflammation response in the footpad or lungs when the mice were challenged with ovalbumin. However, consumption of transgenic a A1 and ovalbumin together promoted a strong ovalbumin-specific antibody response and predisposed the mice to inflammation when challenged with ovalbumin in both the footpad and the trachea. This suggests that transgenic a A1 did promote reactions to other proteins. In confirmation of that, levels of antigen-specific IgG against other proteins such as pea globulins, lectin, and vicilin-4 were also significantly higher in the serum of mice fed transgenic pea than mice fed non-transgenic pea.
Wider implications on the safety of transgenic proteins that must be addressed
The transgenic pea involved gene transfer between plant species, and is generally thought to be much safer compared with the cross-kingdom gene transfer – bacteria to plant – involved in the GM food crops that now cover tens of millions of hectares worldwide.
A harmless bean protein expressed in transgenic pea caused inflammation in mice, and research showed that the most likely reason is because the protein is processed differently in peas. Such post-translational processing of proteins is well known to be species-specific, and as genetic modification almost invariably involves cross-species transfer of proteins, one must expect transgenic proteins to differ structurally from the native proteins as a matter of course. Are they also likely to provoke immune reactions as a result ?
It would not happen in every case, as the researchers have found that neither transgenic lupin sunflower seed albumin, nor transgenic chickpea a A1 gave the same results as transgenic pea a A1. But how frequently could it happen?
“Currently, we do not know the frequency at which alterations in structure and immunogenicity of transgenically expressed proteins occur or whether this is unique to transgenically expressed aA1.” The researchers admitted.
Furthermore, when consumed with other proteins, the transgenic pea protein promoted immunological ‘cross-priming' against those proteins, so that the mice developed specific immunological reactions to them as well. In other words, the transgenic protein can provoke generalised immune response to multiple proteins in the diet, whether transgenic or not.
The previous instance of a GM project being abandoned was the transfer of a Brazil nut allergen into soya [3], and it involved a known allergen. The present case involves a protein that has all the appearance of being harmless.
As yet, no other GM crop, especially those already out there in the fields and in our food and feed, has been tested in this way. This must now be done. Meanwhile, there must be a ban imposed on all GM food and feed.
References
“GM crops scrapped as mice made ill”, Selina Mitchell and Leigh Dayton, The Australian, 18 November 2005. http://www.theaustralian.news.com.au/common/story_page/0,5744,17283002%255E2702,00.html
Prescott VE, Campbell PM, Moore A, Mattes J, Rothenberg ME, Foster PS, Higgins TJV and Hogan SP. Transgenic expression of bean a-amylase inhibitor in peas results in altered structure and immunogenicity. J Agricultural and Food Chemistry 2005, 53, 9023-30.
Nordlee JA, Taylor SL, Townsend JA, Thomas LA & Bush RK. Identification of a brazil-nut allergen in transgenic soybeans. The New England Journal of Medicine 1996, March14, 688-728.
Sent to:
Mr. Hamdallah Zedan, Executive Secretary, Secretariat of the Convention on Biological Diversity, secretariat@biodiv.org
Cc: Mr. David Cooper, Senior Programme Officer – Interagency and Program (UK and Northern Ireland), david.cooper@biodiv.org
Mr. Geoffrey Podger, Executive Director, European Food Safety Authority Geoffrey.podger@efsa.eu.int
Cc: Mr. Herman.Koeter, Director of Science, European Food Safety Authority, Herman.koeter@efsa.eu.int
Dr. Harry Kuiper, Chair of the GMO Panel, EFSA,h.a.kuiper@rikilt.wag-ur.nl
Colin Ross, Food Standards Agency, UK, colinRoss@foodstandards.gsi.gov.uk
Cc:Elliot Morley MP, Minister for the Environment, Emorley@aol.com
Rt. Hon Michael Meacher MP, meacherm@parliament.uk
Canadian Food Inspection Agency, Plant Products Directorate, Plant Biosafety Office, pbo@inspection.gc.ca
Cc:Hon Andrew Mitchell, Minister of Agriculture and Agri-Food and Minister of State (Federal Economic Development Initiative for Northern Ontario), Mitchell.A@parl.gc.ca
Mr. Mike Johanns, Secretary of Agriculture, USDA, United States Mike.Johanns@usda.gov
Cc: Dr. Ron DeHaven, Animal and Plant Health Inspection Service Ron.DeHaven@usda.gov
Mr. Stephen L. Johnson, Environment Protection Agency, USA johnson.stephen@epa.gov
Curious...the 1 yr target in Yahoo has been reduced to $3 from $3.50...no details available as to why or which broker did it...(rodman or SGC)
Being a lurker, my 2 cents...
While I join others in thanking Dew for excellent DD, the street guys haven't noticed GTCB yet. The attendance in last CC was pathetic. So until the street shows up to ask questions in CC, we won't see any traction baring some partnership news on Atryn.