Genetically
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21 April 2000

Table of Contents

Fraud Suspected in Approval of Synthetic Milk Hormone
Effects of Klebsiella planticola SDF20
prostitute journalism: "Unpalatable truths" - New Scientist, April 17, 1999
[GSN] GE drugs: Class action - insulin
Diabetes: Bellagio Report 1996
Scientific Information for the Bellagio Report, April 1996
Hopes Grow for Hybrid Rice to Feed Developing World
corn promoter mutations from insertion

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Date: 18 Apr 2000 14:26:47 +0100
From: jim@niall7.demon.co.uk

Lets hope this one isn't an April Fool. Regards Jim Mc Nulty

Fraud Suspected in Approval of Synthetic Milk Hormone

Fairview Industries, April 18, 2000

BLUE MOUNDS, Wis., April 17 /PRNewswire/ via NewsEdge Corporation -

The following was released today by Fairview Industries:

April 26, 1999, following a Congressional inquiry by Rep. Scott Klug of Wisconsin (ret.), FDA officials handling recombinant bovine growth hormone were accused of fraud by Dr. Bill von Meyer before a senate investigational committee in Canada. The incident involved FDA advising the public 1/24/96 on CBS Morning that the hormone known as rBGH was tested as much as a human drug. Klug's inquiry showed critical tests and data were omitted and that the milk from rBGH-treated cows was not health tested at all. FDA tried to defer answering the Congressional letters of inquiry while DHHS officials resorted to milk mustache ads to create a diversion from the data. Klug was concerned when he received an FDA letter stating rBGH had already been approved in Canada when it had actually been rejected in Canada.

The inquiry was initiated by Dr. Bill von Meyer, former vice-president of a large genetic engineering firm in the USA. von Meyer, Ph.D Purdue University and noted developer of some of the most potent chemicals for crop disease control, found a systematic omission of critical tests in rBGH approval. However, the most serious matter facing the public was the failure to find and discuss the diabetes risks posed by rBGH milk and the complete failure to test rBGH milk for health effects in diabetes.

Bovine growth fragments were found to enhance diabetes in humans by Martin Sonenberg (J. Metabolism 1965). And tests at South Dakota State showed that proteins from cow serum increase in rBGH milk (Dairy Sci. 72(6), 1989). Tests in the early 1990's in Europe and Canada by the Toronto Hospital for Sick Children and others have shown that specific proteins in cow serum cause the formation of antibodies toxic to the pancreas of the children prone to the disease. The rBGH milk hormone would thus be highly suspect as a risk for children drinking unlabeled milk. Summary data on these matters were presented at a Nov. 18, 1999 public hearing on genetically modified foods in Chicago.

To date no federal action has been taken and state health officials in Wisconsin who were advised during the Klug inquiry acted to suppress the concerns. A report surfaced at the Canadian hearing on rBGH which clearly showed that rBGH itself would form antibodies in rat blood serum after oral feeding of the hormone but the long term health effects were not determined. To date all chronic health tests (long term tests) were omitted on rBGH, rBGH milk and no study of what happens to rBGH fragments was done. At the request of Congressman Klug, Dr. von Meyer interviewed FDA on July 2, 1998 to establish these facts in the office of the Congressman. Diabetes currently accounts for between 15-20% of all USA medical costs (communication from Am. Diab. Assoc. 1996)

SOURCE Fairview Industries, Inc.

CONTACT: William von Meyer, Ph.D., President of Fairview Industries, Inc., 608-437-6701


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Date: 19 Apr 2000 10:01:41 +0100
From: "j.e. cummins" jcummins@julian.uwo.ca

Those writing about GM crops and safety testing may appreciate the reference:

Effects of Klebsiella planticola SDF20

Applied Soil Ecology Vol. 11 (1) pp. 67-78
Copyright © 1998 Elsevier Science B.V. All rights reserved.

Effects of Klebsiella planticola SDF20 on soil biota and wheat growth in sandy soil

Authors:

M.T. Holmes a), E.R. Ingham a), J.D. Doyle b), C.W. Hendricks c)

a) , Oregon State University, Department of Botany and Plant Pathology, Corvallis, OR 97331-2902, USA
b) , ManTech Environmental Technology, Inc., 1600 S.W. Western Blvd., Corvallis, OR 97333, USA
c) , The National Health and Environmental Effects Research Laboratory, Western Ecology Division, US EPA, Corvallis, OR 97333, USA

Received 18 February 1997; Accepted 28 March 1998

Abstract

The potential for ecological effects to occur after the release of genetically engineered microorganisms is a global concern and the release of biotechnology products must be assessed on a case-by-case basis. In this research, a genetically engineered strain of Klebsiella planticola (SDF20) bacteria was added to microcosms containing sandy soil and wheat plants to assess the potential for effects on soil biota and plant growth. One half of the soil treatments in this study contained wheat plants to compare some effects on growing rhizosphere communities in the experimental system.

When SDF20 was added to soil with plants, the numbers of bacterial and fungal feeding nematodes increased significantly, coinciding with death of the plants. In contrast, when the parental strain, SDF15 was added to soil with plants, only the number of bacterial feeding nematodes increased, but the plants did not die. The introduction of either SDF15 or SDF20 strains to soil without plants did not alter the nematode community. No effects were observed on the activity of native bacterial and fungal communities by either SDF15 or SDF20. This study is evidence that SDF20 can persist under conditions found in some soil ecosystems and for long enough periods of time to stimulate change in soil biota that could affect nutrient cycling processes.

Further investigation is needed to determine the extent these observations may occur in situ but this study using soil microcosms was the first step in assessing potential for the release of genetically engineered microorganisms to result in ecological effects.

Keyword(s): Genetically engineered microorganisms (GEMs); Klebsiella planticola; Soil ecology; Ecological effects

© Copyright 1999-2000, Elsevier Science, All rights reserved.


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Date: 19 Apr 2000 16:03:46 +0100
From: Robert Mann robt_m@talk.co.nz

prostitute journalism: "Unpalatable truths" - New Scientist, April 17, 1999

This is a gross misrepresentation of Pusztai's expts.
See his article in the April 'Ecologist' (which says www.theecologist.com is available but I disbelieve that).

I have interspersed some comments.

R

New Scientist, April 17, 1999

Unpalatable truths

By Debora MacKenzie

Demanding proof that genetically modified foods are safe is all very well, but without a rational system for testing conventional foods, we may never get it

EARLIER this year, Britain was rocked by claims that genetically modified foods are dangerous. Arpad Pusztai, a biochemist who used to work at the Rowett Research Institute in Scotland, said he had shown that GM potatoes were harmful to rats because of their genetic modification alone. Were the GM potatoes toxic? On the basis of Pusztai's evidence, it's impossible to say.

This is false. There were proper controls, and the GM potatoes did harm which was not done by the same gene product simply added to the potatoes.

In fact, his results support only one obvious conclusion: rats hate potatoes.

This caricature has been spread by people who should know better. The GM potatoes harmed several organs when control expts showed no such harm.

Pusztai fed separate groups of rats on normal or GM potatoes to see if the GM food had different effects. That's good, basic toxicology.

Debra fails to describe the basic design of the expt, as I have just briefly done. This is, at best, rotten journalism.

Unfortunately he couldn't make the animals eat enough potato, so they were malnourished no matter which kind they were eating.

The weight gain was significantly less in the GMF-fed rats. That the same concentration of the same toxin (snowdrop lectin) did no comparable harm when simply added rather than biosynthesized by GM is a strong hint that the GM spuds were toxic in some novel way.

According to toxicologists who examined the data,

who understandably do not want to be named – scientists, huh?!

changes in their organ weights and immune reactivity showed no unambiguous association with genetic modification (This Week, 6 March, p 13).

More biased journalism – the large team of scientists who examined the data affirmed AP's tentative conclusions were warranted.

Starvation or known toxins in raw potato were the most likely culprits for any changes seen in the rats. These experiments reveal a serious problem that is only now being grasped by the biotechnology industry: standard toxicology tests don't work for food. It is often difficult to feed lab animals enough GM fodder, whether or not they find it palatable, to see if it has undesirable effects compared with unmodified food. Essentially, animal models are not sensitive enough to reveal small differences between modified and unmodified foods.

This is more subtly misleading. In order to justify this conclusion, one would need to examine how many animals would be needed, on a mixed diet designed to avoid the 'one component' problems which Debra points to. She shows no signs of having considered these quantitative aspects. The matter is inherently a quantitative one.

Nonstarter Even if you manage to get animals to eat enough test food, you risk changing their diet so profoundly that even those eating unmodified food will be abnormal. For all but the most blatantly toxic GM foods,

such as Pusztai stumbled upon (as the RS etc refuse to admit)

this may make it impossible to draw meaningful conclusions from such experiments. Politicians, taken aback by huge public mistrust of "Frankenfoods", are also realising that safety testing of these foods is not straightforward.

nobody said it was straightforward – just that it should be contrived, developed, and carried out BEFORE unmonitored feeding to humans.

In Britain, the Cabinet's biotechnology committee has commissioned a report on the human health implications of GM foods from the government's Chief Medical Officer and Chief Scientific Adviser, due to be published this month.

big of 'em

A Cabinet Office memo, leaked by Friends of the Earth, asks: "Why don't we require a pharmaceutical-type analysis of the safety of these foods, with proper trials?" But as the problems to date have shown, the proposition is a nonstarter.

This conclusion is not at all justified by anything Debra mentions –or in any other way. It is a bald assertion of propaganda.

So how can we check the safety of GM food? Scientists from the 29 industrialised countries of the OECD concluded at a meeting in Paris in December that a whole new approach is needed. In September, they will meet again to start drawing up ways of carrying out such checks.

oh – but according to Debora they'd be wasting their time.

They are up against some serious logistical problems. Harry Kuiper of the State Institute for Quality Control of Agricultural Products in Wageningen, Netherlands, tested a GM tomato by freeze-drying it and feeding so much to rats that each got the equivalent of 13 of fresh tomatoes a day.

[here I must wonder whether the transcription I'm commenting on is fully precise]

Any more, and they would have been poisoned by the basic nutrients, such as potassium, in the tomato powder. "But toxicologists still said we hadn't fed them enough to get a meaningful result," says Kuiper.

I disregard this rumour.

The usual approach for testing a new food additive, for instance, is to feed it to a rat until a toxic effect is observed. That way, you get an idea of the nature and threshold of any toxicity. But with tomatoes, the researchers never managed to reach that threshold. In standard toxicological terms, says Kuiper, they have not been adequately tested. Others would argue that if such large amounts are harmless, the food cannot reasonably be called toxic.

This is a very crude caricature of the relevant science. Delayed harm – cancer, mutations, malformations in utero, and mental damage – can occur at doses that produce NO acute toxicity. Every student of toxicology knows this; but Debra does not want to know. In the vernacular sense, i.e. the level of New Scientist, these forms of delayed harm come under the rather vague term 'toxic'. Kuiper knows this full well.

Nonetheless, these difficulties mean that GM food developers usually avoid testing whole foods. Instead, they try to isolate the changed portion and test that. As an example, Roy Fuchs, head of scientific affairs at Monsanto, one of the world's biggest developers of GM food, quotes potatoes carrying a gene for the Bt toxin, an insecticide normally produced by Bacillus thuringensis. Monsanto sells its Bt potatoes in the US and is applying for a European licence. Fuchs says that the potatoes, like all genetically engineered plants so far, do not produce enough of the product of the novel gene for it to be isolated from the plants themselves and tested.

As a biochemist I refuse to believe this. To purify the protein in question would not be beyond Monsanto labs' abilities. It is claimed to be abundant enough in the potatoes so that the whole plant is acutely toxic to the Colorado beetle; are we to believe there isn't enough of the toxic protein to purify and examine it?

"So we put the novel genes in bacteria, produce the gene product and test it by conventional methods." However, the protein made by the bacteria may not be the same as that made by the plant, especially in its potential to cause allergy.

Dead right – so please do the proper if more tedious thing.

The production of a novel protein is only one of the potentially harmful changes that occur in when a foreign gene is inserted into a plant. Because the positioning of the novel gene within the plant's DNA is essentially random, it may alter the plant's expression of its own genes –ith unpredictable effects.

Debora is suddenly turning up trumps! This is one of the more important points denied by the gene-jockeys.

It is this kind of change that stymies conventional toxicology. Food is a complex mixture of substances that occur in different quantities in different varieties of crops and in the same variety grown under even slightly different conditions. When is a change in one or several of those substances a problem? Unfortunately, says Peter Kearns of the OECD in Paris, no one has ever tested conventional food for toxicity, so no one quite knows where to start.

– so when a leading scientist tried to make a start, he was ruthlessly suppressed by people who don't want to start and instead are frozen in the '3 wise monkeys' pose. But in reality, what you don't know may very well hurt you. Lack of evidence is NOT proof of safety (Mann 1972).

One exception is potatoes. Conventional plant breeders in the US and the Netherlands test new potato varieties for elevated levels of known toxins such as solenines.

a small point, but I think offhand that this word is 'solanin(e)s'.

French breeders do not –nd there are no legal requirements in any country to do so. And that still leaves toxins in GM foods that we may not yet know about. "We have to think through these things case by case," says Kearns, starting with a better understanding of what is in normal crops.

sounds good – but incompatible with the suppression of AP which Debora is trying to legitimize.

Kuiper's institute is working on a screening test that detects differences in the pattern of messenger RNA molecules produced by normal and transgenic tomatoes. The hope it that this will provide a fast way to see if there have been large changes in gene expression. The method can reliably detect differences between red and green tomatoes –hich is encouraging, says Kuiper, because green ones produce more toxins.

Key differences The team has also compared the chemicals synthesised by normal and transgenic plants by looking at their nuclear magnetic resonance (NMR) spectra. Nearly every chemical compound in the plant produces a characteristic "fingerprint" of peaks. The screening test revealed that there were up to eightfold differences in concentrations of sugars, amino acids and various unidentified compounds. Impressive as this sounds, it may not be significant: Kuiper notes that there were greater differences between unaltered tomatoes grown in different conditions than there were between GM and normal tomatoes grown in identical conditions. A better way of exploiting NMR might be to use it to find substances that differ in transgenic foods and then to test these substances in, for example, cell cultures, to see if the changes could be harmful. The need for such tests may be soon be pressing. But when crops are engineered to produce a number of desired nutrients or "nutraceuticals", changes in the plant's own gene expression could become much more complex and their potentially toxic effects harder to test.

This line is rather subtle. Instead of pressing on with development of actual toxicology which AP began, retreat into years of indirect chemical analysis – while the untested foods are fed on a large scale to humans and animals, and no studies are done to look for any possible harm. The Germans 6 decades ago might have done such a thing to, say, Ukrainians or other 'subhuman' Slavs; the glorious free enterprise West, and the 'communist' People's Republic of China, now think their own people are suitable subjects for this unmonitored experiment. Is there any precedent in all of history for this version of ethics?

However, proponents of GM foods point out that whichever direction food testing goes, the subtly altered products on our plates will have been tested far more thoroughly than any conventional food.

This sentence is worth special study. Note the verb. You can only 'point out' something that is real, well established, not significantly contentious. But the claim for which Debora uses this verb is very very far from that status. Just change the verb to 'claim' – which would be accurate – and see the difference. In this exercise you will begin to glimpse the power of the depraved trade PR.

After all, even ordinary kidney beans are poisonous if undercooked.

This is a tiresome diversion. We know there are other poisons! This is not relevant to the ostensible topic of this article.

Dozens of people die each year from cyanide from peach seeds. Manioc, the staple diet of millions, had to be grated, squeezed and cooked to drive off the cyanide before improved varieties became available.

BTW it would be handy if someone would check the facts of this para. It's news to me that current manioc (cassava) is devoid of the cyanide. Indeed a favourite version of the image that gene-jockeys are deeply concerned to help the poor is the claim that they are about to rejig cassava by GM to decrease the cyanide content.

And some of the most notorious food-linked poisons, such as aflatoxins in grain, do not come from the food but moulds that infect it. In the comparison between modified and unmodified foods, nothing is clear cut. And testing is never simple.

Note Debora's modus operandi: begin with confident assertions of fact, for the purpose of denigrating AP and his school of thought, but then fade out by emitting a fog of doubt & confusion, pretending there are no facts ("nothing is clear cut").

This is one of the more obnoxious pieces of PR that I have seen. I despise it.

R

--------------------------
Robt Mann consultant ecologist P O Box 28878 Remuera, Auckland 1005, New Zealand (9) 524 2949


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Date: 20 Apr 2000 16:11:22 +0100
From: jim@niall7.demon.co.uk

I believe that this could turn out to be a very crucial case. G/E Insulin has long been touted as the man made cure all, and recombinant heaven. I have read many articles about the problems of transition for uses, as well as many not be informed of the change. For the G/E Industry this will certainly send shock waves right back to the investors, if G/E Insulin isn't a safe bet for those pension funds what has biotech got that IS SAFE?
Jim Mc Nulty. Sorry if this has been circulated previously, though I havent seen it before, myself.

[GSN] GE drugs: Class action - insulin

From: Colleen Fuller cfuller@telus.net
http://www.netlink.de/gen/Zeitung/2000/000414a.html

A couple of days ago a class action suit was launched in New Mexico against Eli Lilly and Novo Nordisk, manufacturers of insulin. The suit alleges that the companies removed animal insulins from the market knowing that the genetically engineered products they had introduced to the market caused people with diabetes terrible and potentially life-threatening problems.

Insulin is the first GE drug ever marketed anywhere in the world. As the law suit states, neither company conducted adequate clinical trials prior to getting approval from the FDA. Lilly, it says, used chronic drug users and chronic alcoholics, thereby skewering the results of the tests. The suit doesn't say, but many others have, that the absence of animal and human clinical trials is a problem not only in the US, but in country after country after country. In Canada, one of them (I'm not sure which) used 12 nondiabetic men to test the safety of the GE insulin. I believe it was the British Medical Journal which called for long-term clinical trials involving at least 3900 people, with substantial follow-up.

Now there are growing concerns about the unknown long term affects of genetically engineered insulin. According to a suppressed study undertaken by the British Diabetes Association just before Lilly became a sponsor, some 15-20 percent of diabetics complained of serious side effects, including reduced hypoglycaemic awareness (which is potentially deadly), arthritis and myalgia like symptoms, weight gain and other symptoms. In the US, several diabetics have confronted lawsuits for negligence after going into a coma while driving because they were not aware they had become hypoglycaemic.

The class action suit is very important because it's the first time anyone has taken on drug manufacturers on inadequately tested GE drugs. One question that it raises is: what is adequate testing? How long does it take to understand the long term consequences of genetically engineered drugs?

It also should be of interest and concern to folks fighting on the GE food front.

Colleen Fuller


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Date: 20 Apr 2000 16:11:22 +0100
From: jim@niall7.demon.co.uk

Accompanying Scientific Information

Diabetes: Bellagio Report 1996

by the International Team Residency
http://www.swissdiabetes.ch/~fis2/englvers/bellagio.htm

Recommendation

"The need to enable people requiring insulin to have an informed choice of insulin treatment"

supported by the Rockefeller Foundation, New York, USA

The welfare of people with diabetes depends on their active participation in their care. To achieve this active participation the patient must have information about benefits, risks and alternatives concerning treatment and must have appropriate facilities available to make a free choice.

New research has made possible an overall understanding concerning differences in warning symptoms of hypoglycemia when using genetically produced human insulin and natural animal insulin.

The debate on these differences has continued since the introduction of treatment with human insulin and, unfortunately, very often the patients' experiences have been classed as "only anecdotal" and of little value. Evidence supporting these experiences demonstrates neurophysiological differences during hypoglycemia in human and animal insulins.

Research has already demonstrated that human insulin has no clinical advantage for patients and that it has a faster absorption and consequently a shorter duration of action, so accounting for the greater fluctuations in blood-glucose levels. However, it has been the general view that because of its exact similarity to endogenous insulin, human insulin should be the insulin of choice for all.

Based on the new understanding of the information from the neurophysiological studies which clearly support the reported adverse reactions to human insulin by many patients, we recommend:

  1. That this latest information be relayed to those living with insulin dependent diabetes. This will enable those experiencing impaired or reduced warning symptoms of hypoglycemia or reduced feelings of well-being and safety to re-examine their choice oh human or animal insulin. This choice will then be based on both scientific evidence and the reported experiences of patients;

  2. That this information be reported to Government Health Departments, WHO, IDF, Diabetes Associations, Physicians and all diabetes health care professionals throughout the world;

  3. That when insulin is needed, animal insulin should be considered as first choice treatment for all those where hypoglycemia may be of special concern.

    This may include the following:

    1. Children;
    2. The elderly;
    3. Those reportingsevere and/or frequent hypoglycemia;
    4. Those with severe cardiovascular disease or long term complications;
    5. Those who do not have access to frequent blood-glucose monitoring, eg in developing countries

  4. That animal insulin
    1. remain available in all countries which presently have that facility;
    2. is re-introduced into countries in which it is no longer available or in which it is no longer available through the normal prescribing mechanism;
    3. for insulin pen becomes available again to provide equal choice for patients and physicians

  5. That in future greater recognition should be given to the value of patient experiences in relation to adverse drug reactions.

Rockefeller Study & Conference Center

I-22021 Bellagio (Como), Italy

April 8, 1996


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Date: 20 Apr 2000 16:11:22 +0100
From: jim@niall7.demon.co.uk

Scientific Information for the Bellagio Report, April 1996

"Human Insulin Hypoglycaemia Unawareness: Accumulated Evidence on the Phenomenon"

Sections:
Introduction
Fundamental practical design mistakes
Conclusions
Suggestions
References

Introduction

A Debate on the Well Known Topic of hypoglycaemia unawareness has been going on since the introduction of animal insulin 75 years ago. A few patiefts, mainly insulin-dependent, have suffered from insulin hypoglycaemia unawareness (abrupt severe hypoglycaemia without warning symptoms) over all these years. This debate has risen sharply since the first publication of an apparent sudden rise of this hypoglycaemia syndrome linked to human insulin in 1987 1,2, later confirmed by controlled studies with so called human (HI) vs porcine (PI) insulin from various diabetes centres. 3,4,5.

Many diabetes care professionals around the world do continuously observe differences between human and animal insulin in clinical practice: unawareness of hypoglycaemia symptoms, unstable diabetes control, increased severity of hypoglycaemic episodes without warning symptoms. Human insulin is still one possible explanation for the so called 'dead in bed syndrome' (approximately 50 sudden unexplained deaths in young insulin-dependent diabetics, going to bed in apparently good health and later found dead in an undisturbed bed) 6,7,8. The full explanation still remains unanswered.

Since the introduction of human insulin of recombinant DNA origin in 1982 the official FDA(USA) labelling carries a warning 9. In 1991 the warning was highlighted by the FDA's mandate imposing the use of bold print.

'A few patients who experienced hypoglycemic reactions after transfer from animal-source insulin to human insulin have reported that the early warning symptoms of hypoglycemia were less pronounced or different from these experienced with their previous insulin.'

Recent research has shown important new evidence in hypoglycaemia effects in the brain explaining the loss of awareness of hypoglycaemia in insulin requiring diabetic patients 10. It also provides another very important piece of the jigsaw puzzle in understanding the specific loss of hypoglycaemia awareness in a subset of human insulin consumers.

We are pleased to report that now there is also a logical neurophysiological and pharmacodynamic explanation for the phenomenon of

'human insulin hypoglycaemia unawareness'. We hope all health care professionals will be able to accept that these new findings show a mechanism to explain differences between these two species of insulin, and that these are significant for a substantial number of insulin users – 'that the awareness of changes in central nervous stimulus processing (being stronger after PI than HI) may serve as a first subjective cue for an acute impending hypoglycaemia'11.

Relevant research demonstrating a mechanism for the difference in hypoglycaemic awareness between human and animal insulin (and practical information)

Although it is difficult for many of us to understand this, in two large collections of data held by the British Diabetic Association and the Insulin Dependent Diabetes Trust, cognitive symptoms like these were reported with remarkable consistency, either by patients or by their families, and the majority of these subjects (or carers) reported these difficulties resolving when the patient changed back to animal insulin, irrespective of the duration of treatment with human insulin (Posner T.R.: 3000 letters (384 analyzed) British Diabetic Association 1992. London)

Whether we fully understand these phenomena or not, we must listen to these opinions as patients have very little reason to lie and patient satisfaction, well-being and safety are key factors in diabetes care.

Finally because the numbers are quite large, these reports and the ongoing research are very unlikely to have no foundation.

Fundamental practical design mistakes

Fundamental practical design mistakes in many published scientific studies comparing human and animal insulin

We need to examine how reliable scientific research is to account for the differences that seem to occur between insulin-research and every day use of insulin.

  1. Most commonly not recognizing the effect study conditions have on changing the diabetic patients' level of care they take with their control – this is often subconscious. This practical effect may be difficult for researchers to understand and it is probably only truly understood by those living with the condition.

  2. Patients entered into a trial are often not representative of the population with the disorder36. Numbers of registered participants in research studies, the reasons for non participation and the real drop-out rates are either not published or under-reported 37,38.

  3. Unawareness studies involving self reporting of hypoglycaemia symptoms without recording of self measured blood glucose levels can only be of limited value as the patients may already have some degree of unawareness. Studies which include family members' observations have more value but symptomless hypoglycaemic episodes can still be missed e.g. nocturnal hypoglycaemia which goes unnoticed 37,39,40.

  4. Studies which are obviously atypical of everyday life:

    1. Where the follow up visits to the diabetic clinic are every 2 to 4 weeks 37,38,40. In normal life visits are commonly every 26 to 52 weeks. Recording study events by questionnaire can increase the usual consultation time compared to routine visits.

    2. Where the number of home blood glucose tests are increased by up to 50% per week 40.

    3. Where the insulin species is randomly changed every 4, 6 or 12 weeks 38,41,42. In addition to this, IDDT's analysis of case reports show that the adverse reactions to human insulin took on average 1.1 years to be recognised after starting to use human insulin 12,43.

    4. Where acute hypoglycaemia is induced by intravenous infusion, with the patient being maintained in a prone position anticipating hypoglycaemia and with an intravenous canula maintained in their arm, the symptoms of hypoglycaemia are then recorded under these conditions. Hypoglycaemia in everyday life is where the patient is preoccupied with work or pleasure and the 'hypo' is neither gradual nor predictable 41,42.

    5. Perhaps the most significant error is the failure to realize that hypoglycaemia itself has been shown to produce loss of warnings for several days or longer, therefore hypoglycaemia occurring before the study (of which the patient may be unaware) or indeed slow hypoglycaemia induced by the study itself, may cause loss of warnings, regardless of insulin species 33.

It is not wholly surprising that these studies show no difference between human and animal insulin. Common sense suggests that if patients complain of loss of awareness in everyday conditions 43 then a study must test for this under these conditions.

The last place one can expect a result that is valid for extrapolation to everyday life is from a slow glucose clamp technique procedure under laboratory conditions.

Conclusions

Human insulin is a useful insulin formulation and many people with diabetes can happily use it. However, a substantial minority of people with diabetes feel safer, have better hypoglycaemia warning symptoms with animal insulin and fewer abrupt hypoglycaemic episodes.

A transfer back to animal insulin brings relief in most instances from severe hypoglycaemic events due to loss of warning symptoms 44.

Patients who have always been on human insulin may find advantages if they are allowed to change to animal insulin 45. At the Liverpool Symposium of human insulin and hypoglycaemia (1992) there was general agreement for carefully designed large field studies. Until such scientific evidence can be available, 'the simple practical advice must be that patients who wish to use animal insulin should be able to have the insulin of their choice' 46.

The balance of scientific data confirms that there are differences between human and animal insulin. Several show advantages with animal insulin in controlled studies also in the elderly despite an intact counter-regulatory response 47 and in numerous case histories. No studies show any clinical advantages of human compared to animal insulin.

Review of literature shows altered cognitive function and reduced autonomic nervous stimulation with human insulin. These observations are in agreement with the recent studies of brain glucose uptake in well controlled diabetic patients 10 and offer an explanation for reduced awareness in some patients experiencing hypoglycaemic events from human insulin treatment.

This explanation comes as a relief to many doctors and patients. Adding to this the many case reports from patients or their families who have experienced or witnessed practical problems with human insulin (Insulin Dependent Diabetes Trust, Draft Report. Feb. 1996) means that the case for saying that human insulin should not be the automatic first line choice insulin for most insulin-dependent or insulin-requiring diabetic patients is proven beyond reasonable doubt. (The International Team Residency, Rockefeller Foundation Center Bellagio, April 1996)

This is in agreement with the rules and ethics of careful surveillance control as proposed by health governments and drug control agencies.

Suggestions

(in addition to those already written in the Bellagio Report).

  1. Animal insulin should be used as the first line treament in most newly diagnosed diabetic patients including the elderly. Exceptions may be made in those requiring pens i.e. poorly sighted, and some children, or those with previous insulin resistance.

  2. If patients on human insulin have unexplainable symptoms such as depression, aggressive behaviour, psychological changes, lethargy, muscle cramps, it may well be worth trying a change to animal insulin for at least 6 months.

  3. Human and animal insulin must remain available in all countries. Patients who are well controlled on human insulin and do not suffer from unaccountable problems should not routinely be changed to animal insulin.

  4. Drug companies should produce animal insulin in pen injectors to give both doctors and patients an equal choice of insulin 46.

  5. Drug companies should again start producing a long acting animal insulin (e.g. Ultralente) which has a much longer tradition for smoother control compared to similar human products (e.g. Ultratard HM) and would enable non-insulin-dependent diabetic patients to have one injection a day. A plea for animal Ultralente has been brought forward also in the United States 48.

  6. All governments should assist all drug companies to ease relicensing of animal insulin, especially the ultralong acting insulins.

  7. In countries where animal insulin has been completely removed, government health departments should assist with the reintroduction of animal insulin as soon as possible.

References

  1. Teuscher A, Berger W. Hypoglycaemia unawareness in diabetics transferred from beef/porcine to human insulin. Lancet 1987; ii: 382-85.
  2. Wolff SP. Trying times for human insulin. Nature 1992; 356: 375-76.
  3. Egger M, Smith GD, Teuscher A. Risk of severe hypoglycaemia in insulin treated diabetic patients transferred to human insulin: a case control study. Br Med J 1991; 303: 617-21.
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© Insulin Forum Switzerland
Last updated October 31, 1997


Top PreviousNextFront Page

Date: 20 Apr 2000 16:25:17 +0100
From: "j.e. cummins" jcummins@julian.uwo.ca

PLANT BREEDING:

Hopes Grow for Hybrid Rice to Feed Developing World

By Dennis Normile

U.S. company builds on successes in China as improved techniques and better management deliver higher yields

LOS BA=D1OS, THE PHILIPPINES – Sant Virmani, who heads hybrid rice-breeding efforts at the International Rice Research Institute (IRRI) here, remembers when the number of scientists interested in the subject could fit into his living room. But this month, organizers of an international conference marking the 40th anniversary of IRRI had to fold back a room divider and bring in more chairs to handle the throng that gathered to hear his talk.

That heightened interest reflects the growing number of researchers who hope that hybrid rice will help feed the billions of people who rely on the crop. "Hybrid rice is really the only [technique] at hand that has proven to boost yields in farmers' fields," Virmani says.

Although rice breeders have created improved, higher producing rice varieties, they haven't been able to take advantage of a natural phenomenon that jacks up the yields of grains such as corn. Thanks to an imperfectly understood effect called heterosis, the first generation, or F1, hybrid of a cross of two different varieties grows more vigorously and produces from 15% to 30% more grain than either parent. But because rice is self-pollinating, with each plant producing its own fertilizing pollen, producing hybrid rice was commercially impractical. Now, 3 decades of effort has produced hybrid rice varieties and commercially viable methods of producing the hybrid seed. "Finally, hybrid rice is ready to take off," Virmani says.

Such a jump is needed because increases in rice yields have leveled off in the 1990s, while the population continues to grow. But others counsel caution. They warn that the quality of the hybrid rice hasn't yet matched that of current varieties and that growing hybrid rice requires changes in farming practices, in particular, the purchase of new seeds for every growing season. "Hybrid rice is not a success story – yet," says Wayne Freeman, a retired agronomist who formerly oversaw The Rockefeller Foundation's food programs in India.

The road to the current progress has been long and arduous. In the late 1960s, Chinese researchers discovered a wild male sterile rice variety. Because male sterile plants don't produce pollen of their own, that allowed researchers to fertilize the plants with pollen from other varieties. Not all crosses work, however. Some produce lots of vegetation but little grain.

Yuan Longping, director of China's National Hybrid Rice Research and Development Center in Changsha, Hunan Province, has spent 2 decades working on breeding this male sterility trait into the indica rice varieties grown in China and improving seed-production techniques. Hybrid rice now covers about 50% of China's rice acreage and accounts for 60% of production.

For a long time, however, China was the exception. Its success rested on its vast pool of cheap labor and heavy government subsidies. Producing hybrid seed requires growing the male sterile line together with a second parental line, which provides the pollen. Large teams of Chinese workers spray the male sterile plants with a growth hormone that induces the panicles, or grain clusters, to emerge from the rice leaf sheath to catch pollen more easily. The pollen has to be shaken loose from the second line by workers dragging ropes or sticks over the plants. In a separate area, the male sterile line must be grown alongside a third line, which provides pollen to reproduce the male sterile line for the next seed-growing season.

However, the lure of potential payoffs has proven irresistible. A hybrid rice project launched by the Indian Council of Agricultural Research has boosted yields from less than 100 kilograms per hectare to about 1.5 metric tons through a painstaking trial-and-error breeding effort that involved more than 1000 experimental hybrid lines. Commercial cultivation began in 1994, and some 150,000 hectares are now planted in hybrid rice. Hybrid rice is also being grown in Vietnam and the Philippines, and scientists in Bangladesh, Sri Lanka, and Indonesia are developing hybrid rice varieties for farmers.

In the United States, an effort in the 1980s by a subsidiary of Occidental Petroleum Corp. fell flat. But in the early 1990s a company controlled by the prince of Liechtenstein picked up the rights to use the Chinese hybrid techniques and plant materials and underwrote a research program by RiceTec Inc. of Alvin, Texas, to commercialize the technology. In addition to transferring the male sterility trait into varieties suitable for the United States, RiceTec has mechanized the seed-production process to eliminate the hand labor used in China.

"We are doing with just two workers what the Chinese are doing with 100," boasts Robin Andrews, company president, who says that the details are proprietary. Last year, field trials in Arkansas and Missouri produced hybrid plots with an average yield 33% greater than a variety of the farmers' choice. As a result, says Andrews, "every one of the farmers who participated in our trials has bought seed to plant this year."

Farmers in other parts of the world remain to be convinced that hybrid rice is better, however. A small study in India by Aldas Janaiah, an agricultural sociologist at IRRI, found that actual harvests often fell short of projected yields and that most farmers do not plan to plant hybrid rice again. And Virmani admits that hybrids require farmers to monitor fertilizer applications more closely and take greater care of the transplanted seedlings. Breeders also need to improve the quality and taste of hybrid rice.

Still, Virmani believes that the growing cadre of researchers around the world will eventually solve those problems. "Ten years ago you couldn't get even 20 people interested in talking about hybrid rice," he says. "Hybrid [rice] research efforts are really just getting started."

* Rice Research for Food Security and Poverty Alleviation, 31 March to 3 April.


Top PreviousFront Page

Date: 20 Apr 2000 17:37:51 +0100
From: "j.e. cummins" jcummins@julian.uwo.ca

corn promoter mutations from insertion

Thursday, April 20, 2000
Prof. Joe Cummins    e-mail: jcummins@julian.uwo.ca

Mutations in the Promoter Genes of Corn (Maize) are Mainly Due to Insertion of Transposons

Corn is one of the most important crops worldwide. It is a grass distantly related to rice and numerous other grains. The genome of corn has genes arranged similarly to other grasses but the crop has more DNA in each nucleus than do other grasses. All grasses have active genes arranged on a chromosome separated by retrotransposons and endogenous (sleeping) virus, corn DNA has about 85% retrotransposons and endogenous viruses. Retrotransposons are retrovirus (replicate by converting RNA into DNA) that lack the envelope gene that allows the virus to escape from the cell, however, retrotransoposons do move around slowly within the genome (the movement is usually by making a copy of the retrotransposon at a different locus).

In the article ,whose abstract is below, mutations were studied in various alleles of a promoter gene of corn. The mutations proved to result from insertion of transposons for the most part. In contrast, the genes that produce protein products ( structural genes) do not usually arise from transposon insertions.

The results are significant for genetically modified (GM) crops because introduction of genes from outside the normal genome activates transposons to and endogenous virus to move. As we have discussed earlier, promoters are hot spots for recombination and insertion of the transposons will alter control properties of the gene that the promoter activates. Unexpected chemical toxins are likely to appear tin transgenic constructions. Furthermore, numerous human genes are being introduced into corn and field tested to be used as pharmaceutical products. The products and their properties are likely to be altered by promoter insertions. Proc. Natnl Acad Sci (USA)Vol. 96, Issue 26, 15007-15012, December 21, 1999


Evolution

The B Gene, A Regulatory Locus In Maize

Major recent and independent changes in levels and patterns of expression have occurred at the b gene, a regulatory locus in maize

By David A. Selinger and Vicki L. Chandler*
Department of Plant Sciences, University of Arizona, 303 Forbes Hall, Tucson, AZ 85721

Communicated by Susan R. Wessler, University of Georgia, Athens, GA, October 25, 1999 (received for review August 3, 1999)

The b locus encodes a transcription factor that regulates the expression of genes that produce purple anthocyanin pigment. Different b alleles are expressed in distinct tissues, causing tissue-specific anthocyanin production. Understanding how phenotypic diversity is produced and maintained at the b locus should provide models for how other regulatory genes, including those that influence morphological traits and development, evolve.

We have investigated how different levels and patterns of pigmentation have evolved by determining the phenotypic and evolutionary relationships between 18 alleles that represent the diversity of b alleles in Zea mays. Although most of these alleles have few phenotypic differences, five alleles have very distinct tissue-specific patterns of pigmentation. Superimposing the phenotypes on the molecular phylogeny reveals that the alleles with strong and distinctive patterns of expression are closely related to alleles with weak expression, implying that the distinctive patterns have arisen recently.

We have identified apparent insertions in three of the five phenotypically distinct alleles, and the fourth has unique upstream restriction fragment length polymorphisms relative to closely related alleles. The insertion in B-Peru has been shown to be responsible for its unique expression and, in the other two alleles, the presence of the insertion correlates with the phenotype. These results suggest that major changes in gene expression are probably the result of large-scale changes in DNA sequence and/or structure most likely mediated by transposable elements.

* To whom reprint requests should be addressed. E-mail: chandler@ag.arizona.edu.