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Novartis Foundation Bulletin

Issue 2, June 2000

Welcome to the second  issue of the Novartis Foundation's e-mail Bulletin. This issue features reports on 

Food for all

(Advancing rice research with cutting edge science 
Symposium 236 27-29 March 2000)

First, some statistics. As a staple food providing roughly one-quarter of the calorie intake of human populations, rice is undoubtedly one of the most important food crops of the world. And the staggering fact is that in many parts of Asia, rice contributes as much as three-quarters of the food intake. During the Green Revolution, between 1970 and 1985, rice production grew at a faster rate than the human population; an enormous achievement brought about by advances in agricultural science. However, since the mid-1980s, rice production has lagged behind population growth, and estimates are that rice harvests will have to increase by some 40 per cent over the next 20 years to meet the increased demand -- the 'yield gap'. Given that there is limited rice production capacity outside Asia, and that many countries in South Asia do not have the resources to buy rice from exporting countries, it becomes clear that the only way to meet this goal is to raise rice yields in rice-producing countries. It is against this background that this symposium was held, at the International Rice Research Institute (IRRI) in the Philippines. IRRI is to rice research what Lord’s is to cricket. With a track record of 40 years of pioneering rice research and a concentration of expert rice scientists, it was the perfect place to hold a meeting that brought together some of the leading researchers in the field to discuss ways in which this yield gap may be bridged.

There is insufficient space here to do justice to all the high quality research that was discussed at the symposium -- I will just focus on a few of the topics that were discussed. Many people will already be aware of the pioneering studies presented by Peter Beyer on the development of 'golden' rice. This is rice that has enhanced vitamin A content, through transformation with two daffodil genes, resulting in yellow grains. This rice, if made widely available, could help the millions of children in Asia suffering from preventable blindness.

Maurice Ku's work on trying to engineer the more efficient C4 photosynthetic pathway into the less efficient C3 rice plant has also attracted a lot of press interest in recent months. Maurice described some of the impressive progress that his laboratory has made using transgenic technology, but the discussion revealed that there are still some severe obstacles to be overcome. 

Kazuko Yamaguchi-Shinozaki described studies showing that in the model plant Arabidopsis, salinity, cold and drought tolerance can be enhanced by transformation with a series of transcription factors, work which holds obvious promise for rice if rice homologues of these genes can be identified. One way to increase yields is by addressing the factors that cause crop losses, such as disease. Along these lines interesting work was presented at the symposium by Jane Parker, Xinnian Dong and Jan Leach, who have been investigating the genetics of defence pathways.

Finally, one topical issue that was raised at the meeting concerned the worrying attitudes of the public towards agricultural  biotechnology, and in particular towards genetically modified foodstuffs. There was no doubt in the minds of the researchers at the symposium that in order to avoid starvation in Asia, the development of transformed (genetically modified) crops is going to be essential in order to bridge the yield gaps. It is a tragedy that the application of some of the groundbreaking and elegant science presented at the symposium may be jeopardized by public sentiment in western nations, who do not suffer food shortages.

Jamie Goode

‘Rice biotechnology: improving yield, stress tolerance and grain quality’ will be published by Wiley in 2001.

For abstracts from the symposium see http://www.novartisfound.org.uk/fp236.htm

AGEing – breaking the bonds

(Ageing vulnerability Symposium 235 29 February-2 March 2000)

For all the claims of anti-ageing creams and therapies, nothing has so far restored the vigour of youth or even delayed the inevitable process of growing old. But, as was discussed at this recent symposium, research scientists have now developed a drug that may rejuvenate hearts and muscles by breaking the stiff bonds between sugars and proteins that are involved in ageing.

Anthony Cerami (New York, USA) first suspected sugar may have an impact on ageing when he began his research in diabetes. As diabetics age more rapidly, excess sugar in blood seemed the likely culprit. Although the sugar in our diet provides us with a ready source of energy, in the body, glucose becomes highly reactive. Acting as molecular glue, sugars attach themselves to the amino groups in tissue proteins to form yellow-brown compounds known as advanced glycation endproducts (AGEs).

Inevitably, with continued glucose consumption, AGEs slowly accumulate, turning our tissues yellow and leathery. Piling on yellow-brown pigment in the teeth, bones and skin is mostly harmless. But long-lived structural proteins, such as collagen and elastin stiffen irreversibly. The result is a constellation of body changes -- thickened arteries, stiff joints, feeble muscles, failing kidneys and lungs -- the hallmarks of old age. In diabetic patients, as a result of high blood sugar, AGEs accumulate faster. Indeed, there are similar amounts of AGEs in collagen from elderly people and diabetics. 

Cerami’s quest has been to find a compound to tie up excess glucose and thus slow down premature ageing. The food industry provided him with an unexpected source of inspiration. Since 1912, food chemists have known that extreme heat such as an oven, forms tight chemical bonds between sugars and proteins -- the same reaction as takes place inside the body when AGEs form. This Maillard reaction turns roasted turkey, toast, and coffee beans golden brown. Crucially, food chemists also knew that chemical inhibitors would prevent browning, keeping food and beverages looking fresh.

Profiting from this knowledge, Cerami’s team has come up with drugs he calls ‘breakers’, which can undo the crosslinking once it has already taken place. The ‘breaker’, dimethyl-3-N-
phenacylthiazolium chloride, ALT-711, has been designed to shatter protein crosslink bonds, thus attenuating the pathological conditions that accompany AGEs. Diabetic animals, old dogs and elderly rhesus monkeys given the compound daily for three weeks yielded spectacular results. ‘The heart and major arteries which were quite stiff become more pliable and elastic, so the heart can pump more blood -- similar to what you’d see in a young animal.’

Cerami envisages multiple uses for breakers in pathologies that involve stiff tissues. For example, in glaucoma, to increase the elasticity of the draining canal and prevent the build up of pressure, to halt the decline in lung function that occurs with age, to make the prostate more pliable in ageing men, when it enlarges and stiffens, and even to treat ageing skin. Although he warns that it will be at least 10 years until such drugs, currently undergoing clinical trials, are approved for use in humans.

Lisa Melton

The full version of this article is published in the July 2000 issue of Scientific American.

‘Ageing vulnerability’ will be published by Wiley in December 2000.

For abstracts from the symposium see http://www.novartisfound.org.uk/fp235.htm

Deadly decisions

(Gastroenteritis viruses Symposium 238 16-18 May 2000)

Will poorer nations accept a life-saving vaccine that has been deemed unsafe in the USA? In rich countries, diarrhoea is not a killer. But in developing countries, diarrhoea is often a death sentence, especially for young children. The toll is huge: severe gastroenteritis is responsible for a quarter of all deaths worldwide. Rotaviruses are the main agents behind life-threatening gastroenteritis, causing an estimated 45 per cent of severe diarrhoea worldwide.

Water and food contaminated with faeces are the vehicles for these ubiquitous viruses. Even the hygiene-conscious West with the luxury of a clean water supply has been unable to eradicate the lurking threat of gastroenteritis. But the yawning gap in health provision between rich and poor nations becomes painfully obvious in diarrhoeal infections. In rich countries, severe diarrhoea is kept in check by prompt and effective treatment. Whereas in poorer nations, therapy is often too late or difficult to deliver, making vaccination the only feasible option.

A vaccine for rotavirus, RotaShield®, already exists. Unfortunately, it has fallen into an ethical minefield that threatens to keep it away from those who will benefit the most. Albert Kapikian (National Institutes of Health, USA) developed a vaccine that protects against the four most common types of strains. In 1998, after exhaustive trials, the vaccine was licensed by the US Food and Drug Administration. A year later, after tens of thousands of immunizations, the vaccine was withdrawn, when 15 young children were hospitalized for intussusception (a blockage in the bowels caused by the intestine folding over itself).

The task at hand is to ascertain whether the link is real. The odds of developing intussusception without vaccination have never been defined, Kapikian told researchers at the symposium. If the vaccine is finally cleared (the data should be ready by October 2000), it is still unlikely that Americans and Europeans will take kindly to it. In these countries, even the severest forms of diarrhoea are easily treated, so it may be a struggle to persuade mothers to inoculate their children with a vaccine that could prove deadly -- however minute the risk. 

Things are quite different in the poor countries of sub-Saharan Africa, Asia and South America. Every day, rotavirus kills 2000 infants, and the vaccine could cut deaths dramatically. For them, the balance is tipped: the vaccine’s benefits clearly outweigh the risks. The issue puts leaders of developing nations in a precarious position. On the one hand, why accept a vaccine that has been deemed unsafe and withdrawn from the US market. On the other, failing to improve matters for their people when a solution is at hand almost borders on the immoral. Unfortunately, the vaccine has made a false start, and at the moment, the chances of seeing it reversed seem depressingly remote. 

Lisa Melton

‘Gastroenteritis viruses’ will be published by Wiley in 2001.

For abstracts from the symposium see http://www.novartisfound.org.uk/fp238.htm

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