Making formula milk more like mum's
- 14 July 2008 by Jo Whelan
- Magazine issue 2664.
Breast is best. There's no doubt about it. The list of proven benefits grows longer every year. Breastfed babies are not only protected against a huge range of infections, they also enjoy lifelong benefits, from higher intelligence to a lower risk of obesity and diabetes.
The reason, we are discovering, is that breast milk is the ultimate functional food. As well as providing babies with the essential nutrients they need to grow and develop, it also contains hundreds of active components that do everything from targeting dangerous pathogens and boosting the development of a baby's gut to preventing allergic reactions and increasing appetite. What's more, the composition of breast milk changes over time to match babies' needs - levels of natural painkillers called beta-endorphins are highest right after birth, for instance, while levels of most nutrients gradually fall over the first year or so.
Due to its benefits, health authorities recommend breastfeeding exclusively for the first six months of a baby's life, followed by breastfeeding in addition to solid food until children are at least a year old. Yet in the US, just 11 per cent of babies are exclusively breastfed up to the age of six months. In the UK, the figure is just 3 per cent. Despite all the public-health campaigns encouraging new mothers to breastfeed, tens of millions of babies worldwide are raised on infant formula rather than breast milk.
Given that so many babies are getting formula, shouldn't we do everything possible to make it better? Yes, argue some researchers and companies. It is becoming feasible to manufacture human proteins like those in milk, which could be added to formula.
Even in California
"In developing countries this would be of benefit for those who cannot, for various reasons, be breastfed," says Bo Lönnerdal of the University of California, Davis, who studies breast milk and nutrition. "Even in California, in very affluent communities, formula-fed infants have more infections - and are ill longer when they get infected - than breastfed infants. So just about anybody would benefit from a formula that contained more components that fight infection."
Just about anybody would benefit from formula with infection-fighting factors
Like most things to do with formula milk, though, just about every aspect of this idea is fraught with controversy. Can formula really be made more like breast milk? Is it safe to produce breast-milk proteins by genetic engineering? And could enhanced formula do more harm than good by undermining the "breast is best" message?
Mimicking human breast milk is virtually impossible. Besides the fats, proteins, carbohydrates, minerals and vitamins that babies need to survive, breast milk also includes hormones, immune signalling molecules, antibodies and even living immune cells. It also contains live bacteria that help colonise a baby's gut, along with substances that promote the growth of beneficial gut bacteria.
Protective factors
We still have much to discover about what's in breast milk and what it does. For instance, it has recently been found that breast milk contains endocannabinoids that stimulate suckling and appetite - essentially giving babies "the munchies". Earlier this year it was even reported that human milk contains stem cells, although it remains unclear what, if anything, they do.
What we do know is that breast milk helps protect babies against disease in numerous different ways. It contains hundreds of specific substances that provide general protection against infections, ranging from sugars that stop bacteria sticking to gut cells, and fats that disrupt certain kinds of viruses, to an array of signalling molecules that stimulate immune development.
It also includes tailor-made protection in the form of antibodies specific to viruses, bacteria and toxins that the mother has already been exposed to. In breastfed babies, these antibodies help mop up pathogens and toxins in the mouth, throat and gut. The way in which they are produced is highly sophisticated: some milk antibodies are secreted by immune cells that have migrated from the mother's gut to her breasts.
Breast milk also contains living immune cells from the mother, which have been shown to survive in the baby's gut, where they may target pathogens directly. Some even enter the infant's body proper, and might help "educate" its immune system. A mother's milk also appears to teach her infant's immune system what not to attack: it contains potential allergens eaten or even breathed in by the mother, along with factors that tell the baby's immune system not to overreact to them.
Not a good match
By contrast, most infant formulas are made from cow's milk. This also contains active components, but many are specific to cows, the levels differ greatly from those in human milk and they can be damaged during the production of formula. "The proteins in cow's milk formula are quite different from those in breast milk," Lönnerdal says. In fact, not only does formula lack the active components of human milk, it is also not a very good nutritional match (see "Too much of a good thing?").
Yet breastfeeding can have drawbacks, the biggest being that some infections can be passed to babies via breast milk - including HIV. For every six months that an HIV-positive women breastfeeds, there is about a 4 per cent chance of the infant becoming infected. Despite this low infection rate, it's estimated that breastfeeding is responsible for up to half of the 640,000 HIV infections in infants each year. For this reason, the World Health Organization recommends infected mothers avoid breastfeeding if they can safely do so.
The brutal truth, though, is that if you are an HIV-infected mother living in poverty, there is no safe alternative. According to one meta-analysis, formula-fed babies in the developing world are six times as likely to die in the first two months of life as breastfed babies, and continue to be at higher risk throughout their first two years of life (The Lancet, vol 355, p 451). The protective effect is partly due to avoiding contaminated water, but it's also because formula does not provide the same range of protective factors.
So for the babies of poor, HIV-positive mothers, formula feeding can be just as risky as breastfeeding. However, if some of the active components in breast milk were added to formula, some researchers argue, it could save the lives of many children. Illimar Altosaar, a biologist at the University of Ottawa in Ontario, Canada, thinks a whole array of immune proteins could one day be added to formula milk.
Better than breast?
In theory, this could include a wider range of antibodies than any individual woman produces and so might even exceed the protection provided by breast milk in some respects. But this remains a very distant prospect, as human proteins are still difficult and expensive to manufacture.
This is why there's long been interest in the animal versions of human milk proteins, such bovine lactoferrin, which can be produced relatively cheaply. Lactoferrin, found in tears, saliva and other bodily secretions as well as milk, binds to iron, boosting iron uptake and also depriving many bacteria and fungi of the iron they need to grow. The highest concentrations are in colostrum, the early milk produced for newborns.
Bovine lactoferrin is already added to some infant formulas in Japan, South Korea and Singapore, Lönnerdal says. "But it has not really been a full success story." The reason, he and others have shown, is that our gut cells have a receptor specific to human lactoferrin. Lactoferrin binds to this receptor, goes inside the intestine itself and stimulates the immune system. Because bovine lactoferrin does not recognise the human receptor, it is not nearly as potent as the human variety
Many other protein components of breast milk, including antibodies, may also rely on similar recognition. This could be why trials of infant formula which has been enriched with antibodies from the colostrum of cows immunised against human pathogens, such as rotavirus, have produced mixed results.
Human is best
Hence the need for the human versions of proteins. Genetic engineers have taken the first steps towards manufacturing around a dozen protective proteins found in human milk (see "Making human milk"). The two closest to commercialisation are lactoferrin and lysozyme, an enzyme that attacks the cell wall of some bacteria and is thought to act in synergy with lactoferrin.
Human lactoferrin and lysozyme produced in genetically modified rice have produced positive results when added to oral rehydration solutions, which are the main treatment for diarrhoea in developing countries. Diarrhoea kills up to 1.8 million children each year and stunts the development of many more.
A study of 140 children, by Nelly Zavaleta's team at the Institute of Nutritional Investigations in Lima, Peru, found that episodes of diarrhoea were shorter in children who received the solution containing lactoferrin and lysozyme compared with those given standard solutions, and there were no adverse effects. The concentrations of the proteins used were similar to those found in human breast milk. Lönnerdal helped design the study, which was funded by Ventria Bioscience of Sacramento, California, the company that created the GM rice.
As yet, there have been no trials to see whether human lactoferrin and lysozyme have similar benefits when added to infant formula. Even if they do, will such enhanced formulas really enable more poor, HIV-infected mothers to switch safely to bottle feeding? Many experts are doubtful. "You have to ask, what is the scale of the benefit?" says Nigel Rollins of the University of KwaZulu Natal in Congella, South Africa. "This is a relatively expensive option. It doesn't get to the root of the problem, namely helping women make a good decision about feeding in the first place."
Formula for disaster
Although there is a widespread perception among poorer families in South Africa that formula is better than breast feeding, Rollins says, formula feeding by poor mothers can be disastrous. All too often feeds are prepared with contaminated water, and sometimes to the wrong strength. Buying the formula also leaves poor families less money for other food, healthcare and education. Exclusive breastfeeding is still the best option for the children of most poor, HIV-infected mothers, he says. Women need to understand the pros and cons of each option, and make the right choice for their own circumstances.
Where resources are scarce, Rollins says, a higher priority than enhancing formula should be to make breastfeeding safer. For instance, giving antiretroviral drugs to both HIV-infected mothers and their infants while they are breastfeeding can reduce transmission rates. A team at the University of KwaZulu Natal is also exploring giving infants oral doses of a monoclonal antibody designed to stop HIV entering cells. The bottom line is that there are better ways to improve health in poor countries than expensive enhanced formulas.
What about wealthy countries? If companies could produce a product with just a few of the advantages breast milk has over existing formulas, surely parents would welcome it? The catch is that the only way to mass-produce these proteins is by genetic engineering. Although the proteins in these products might have exactly the same effect as the ones mothers would produce themselves if they breastfed, it would be a brave manufacturer who labels their baby milk as "containing genetically modified ingredients" - yet this is what they would have to do in the European Union.
Major hurdle
In both the EU and the US, new ingredients also have to go through an approval process before they can be added to formula. "If these recombinant proteins confer major health benefits, will that convince legislators to approve the products and consumers to buy them? That will be the major hurdle," Lönnerdal says.
Whether or not enhanced formulas ever make it onto the shelves, however, the good news for most parents is that a more advanced and sophisticated food for babies is already available - and it even comes free.
Too much of a good thing?
Adding human immune proteins to infant formula is one way to make it more like breast milk. The most important priority for improving formula, however, should be to modify the protein composition to make it closer to that of breast milk, says Bo Lönnerdal of the University of California, Davis.
Formulas have slowly been improved since they were developed about a century ago as an alternative to feeding babies plain old cow's milk. Since the 1950s, manufacturers have added selenium, nucleotides (the building blocks of DNA) and, most recently, omega 3 fatty acids. Even so, they are still a long way from breast milk.
The biggest difference is that formula milk has roughly 50 per cent more protein than breast milk. Formula-fed babies therefore have higher levels of amino acids in their blood after feeding. As some of these amino acids prompt the release of insulin, some researchers have suggested that they could play a role in excessive weight gain and possibly, later on, diabetes. The studies needed to test this hypothesis have yet to be done, Lönnerdal notes, but adjusting the protein content of formula would be desirable in view of the marked difference from breast milk. "I believe it is too high and should be lowered," he says.
The problem is that the differences in the protein composition of human and cow's milk mean that simply removing the excess protein would leave babies short of some vital amino acids. This could be overcome by adding extra quantities of proteins rich in those amino acids, but this is costly and difficult, and as yet no manufacturer has done it.
Making human milk
Adding human breast-milk proteins to infant formula might have benefits for formula-fed children. The trouble is finding a safe, reliable and cheap way of producing them.
The only way to mass-produce human proteins is to genetically engineer other organisms to make them, and plants are emerging as the most practical option. At least seven human milk proteins have already been produced in modified food crops, mainly potatoes and rice, with more in the pipeline. The leading company in this area is Ventria Biosciences of Sacramento, California. It is growing rice in Kansas which contains human milk proteins which, it hopes, can be added to infant formula and oral rehydration salts.
Rice is particularly attractive, as it rarely causes allergies in humans and is often used as a weaning food. However, several giant agribusiness and food companies have protested at Ventria's plans. The fear is that these transgenic crops could end up in our food chain.
While human milk proteins would pose no danger to those who ate contaminated food, it's the principle that matters, says Karen Perry Stillerman of the Union of Concerned Scientists. "We are against looking at this on a case-by-case basis. We would like medical proteins not to be grown in food crops outdoors, full stop."
Perhaps the ultimate solution would be to create herds of cows that produce human milk instead of cow's milk. Netherlands-based company Pharming already uses cows to produce the human breast-milk protein lactoferrin. However, engineering cows to produce 100 per cent human milk isn't feasible - yet.
Jo Whelan is a freelance science writer based in Oxford, UK