Michelle Berriedale-Johnson reports

Much excitement has been generated by the publication, in the Proceedings of the National Academy of Sciences of the USA (PNAS), of research describing the successful genetic modification of a New Zealand cow (called Daisy...) to minimise her production of the whey protein beta-lactoglobulin, found in all animal milks but not in human milk. Beta-lactoglobulin is thought to account for a significant proportion of cow's milk allergy, especially in children. However, claims that this may the 'solve' the problem of cow's milk allergy are not only very premature but, incorrect.

The work carried out at AgResearch's Ruakura Campus in Hamilton, NZ used a technique called RNA interference which, rather than 'knocking out' the gene, reduced its activity by 95% thereby reducing the beta-lactoglobulin in the whey to 5% or less of its previous level.

'The scientists first tested the process in a mouse model engineered to produce the sheep form of BLG protein in mouse milk. This resulted in a 96% reduction in the sheep BLG protein in mouse milk. They next produced Daisy, a female calf that was genetically engineered to express the same two micro RNAs, this time to target the BLG protein that is also a normal constituent in cow's milk. They then hormonally induced Daisy to lactate. The resulting milk collected from Daisy had no detectable BLG protein and, unexpectedly, also had more than twice the level of the casein proteins that also normally occur in cow's milk.' (From AgResearch News.)

However...

• While it is known that beta-lactoglobulin does trigger allergic reactions in many cow's milk allergic people, especially children, very little is known about what other functions it may have in the body and, therefore, what effects dramatically reducing it might have.

• No one knows what effects doubling the level of casein proteins might have either on the cows or on those consuming their milk.

• It is not known whether or not this milk would be safe for human consumption.

• It is not known what side effects this genetic modification might have on the cows themselves. Daisy was actually born without a tail, which does very occasionally happen in cows but, whether this was in any way related to the genetic modification or purely coincidental is not known.

• Daisy was hormonally induced to lactate but it is not yet known whether such genetically modified cows would be able to lactate naturally.

• It is not known whether it will be possible to breed from these cows, or whether, if it is, the genetic modification will be carried across the generations.

• Genetically engineering cattle is extremely expensive so whether this would ever be a financially viable approach to managing cow's milk allergy is questionable.

But...

• In purely scientific, research terms, this is a very exciting breakthrough. To quote Professor Bruce Whitelaw, Professor of Animal Biotechnology at the University of Edinburgh:

RNAi has a long history of successful application in diverse species from plants to worm – this is the first spectacular report for livestock. RNAi knocks down gene activity, i.e. it reduces gene activity without eliminating it. In this study beta-lactoglobulin levels are reduced to only 5% of original levels. There are currently projects that are attempting to knock out beta-lactoglobulin in livestock which should reduce this protein levels to zero. Theoretically RNAi offers fine tuning in comparison to knock out strategies.

Would it actually be useful?

But even assuming that all those questions could be satisfactorily answered, how useful would this milk be in managing cow's milk allergy? Does it really have, as Professor Graham le Gros, Director of New Zealand's Malaghan Institute of Medical Research says, 'enormous implications due to its potential to reduce the significant impact milk allergies have on our children'?

Cow's milk allergy is notoriously complex with over 30 proteins, and many more component epitopes, implicated in reactions. Beta-lactobulin proteins may be amongst those commonly involved in reactions, especially among children, but they are, in effect, only one of many.

To quote the authors of a helpful paper published in the Journal of American College of Nutrition in 2005, Cow's Milk Allergy: a complex disorder –

'Cow's milk allergy (CMA) is a complex disorder. Numerous milk proteins have been implicated in allergic responses and most of these have been shown to contain multiple allergenic epitopes. There is considerable heterogeneity amongst allergic individuals for the particular proteins and epitopes to which they react, and to further complicate matters, allergic reactions to cow's milk are driven by more than one immunological mechanism. Finally, the incidence and dominant allergic mechanisms change with age, with IgE-mediated reactions common in infancy and non-IgE-mediated reactions dominating in adults...

...Our understanding of the number and nature of allergenic determinants in milk is rapidly improving. It is known that both the allergy triggers in milk and the immune responses to those triggers in allergic individuals are multifarious. For example, most major cow's milk proteins (more than 30 so far) have been implicated in allergic responses, including both casein and whey proteins. Epitope mapping of a number of milk proteins has revealed multiple allergenic epitopes within each protein, both for B cells that produce antibodies, and for T cells that direct both antibody and cell-mediated immune responses. Additionally, there is considerable heterogeneity amongst allergic individuals for the particular proteins and epitopes to which they react. While there is scope for further epitope mapping of milk proteins, the complexity of antigenic determinants in milk is already apparent, as is the scale of the challenge to selectively eliminate them.'

So, even if it were possible to reduce the the amount of beta-lactoglobulin in milk to 5% or less, there is no guarantee that this will prevent allergic reactions in more than a limited number of allergic children or adults.

Lactose intolerance

Meanwhile, genetic modification of proteins will have no effect whatsoever on the lactose sugar in the milk, the sugar being what affects those with lactose intolerance, a very much larger group than those suffering from cow's milk allergy.

So, while congratulations are certainly in order as far as the science is concerned, no one should expect anything much of Daisy in the way of allergen-free milk for a long, long while.

First published in October 2012

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