Canny breeding creates vitamin A-rich maize without genetic modification

Blogging on Peer-Reviewed ResearchOn Thursday, I wrote about a way of genetically modifying carrots to turn them into rich sources of calcium. The method could be more widely used in vegetables to help reduce nutritional deficiencies, but it risks raising the ire of the anti-GM environmentalist camp. But there is another way of altering the genes of crop plants that avoids such controversy, and it’s a traditional one – selective breeding.

Types of maizeBy cross-breeding individuals with desirable qualities, farmers have been tinkering with the genes of both animals and plants for centuries. Traditionally, the process has been a bit messy. Genes don’t always easily translate into physical characteristics, so there is a certain amount of trial-and-error involved.

Now, Carlos Harjes from Cornell University had developed a way of using modern genetic techniques to make selective breeding even more selective. For his first trick, he has developed a variety of maize to combat vitamin A deficiencies. Best of all, no genes were added, tweaked or subtracted in the making of this vegetable – he only used the natural genetic variation within the world’s maize strains.

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Meet the genetically modified super-carrot, now fortified with calcium

Blogging on Peer-Reviewed ResearchFor centuries, mothers have wrongly told their children that eating carrots will improve their vision. The sight-enhancing properties of these iconic vegetables is be a myth (albeit a fascinating one involving Nazis and fighter pilots) but if Jay Morris has anything to say about it, they may soon be better known for building strong bones.

Types of carrotsMorris, together with Kendal Hirschi and other Texan colleagues, has found a way to double the calcium content of carrots through genetic modification, making them a rich source of the element that is so vital for bones

The team loaded their super-carrots with a protein called sCAX1, which pumps calcium into the plant’s cells. The protein originally hailed from the plant-of-choice for geneticists, Arabidopsis thaliana, where it exists in a larger version. Morris’s team lopped off a small piece from its tip that stops the protein from funnelling in more calcium once a certain amount has been reached.

In this shortened form, sCAX1 is relentless in its import of calcium and the researchers have found that it can greatly increase the calcium content of several vegetables including tomatoes, potatoes and carrots. These super-charged vegetables could help to reduce the risk of osteoporosis, one of the world’s leading nutritional disorders, where a lack of calcium leads to brittle bones.

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The effect of GM crops on local insect life

A large study weighs up the existing evidence on the impact of GM crops on local insect life, providing some much-needed scientific rigour to the GM debate.

In Europe, the ‘GM debate‘ about the merits and dangers of genetically-modified (GM) crops is a particularly heated one. There is a sense of unease about the power of modern genetic technology, and a gut feeling that scientists are ‘playing God’. These discontents are stoked by the anti-GM camp, who describe GM crops with laden and fear-mongering bits of unspeak like ‘Frankenstein foods’ and ‘unnatural’.

Bt cotton is better for non-targeted insects than non-resistant crops sprayed with insecticdes.In a debate so fuelled by emotion and personal values, scientific research and a critical analysis of the evidence rarely gets a look-in. But science has to grudgingly admit some blame in this, because there is actually precious little research on the safety of GM crops. And many of the studies that have been done were short-term and poorly replicated.

A lack of research is dangerous. It provides opening for people on either side of the debate to quote single, small studies as canon and brushing aside any research that contrasts with their stances.

Adding evidence to the debate

Michelle Marvier and colleagues from Santa Clara University, California, are trying to change all that. They have analysed over 42 field experiments on GM crops to get an overall picture about their safety. The technique they used is called meta-analysis, a statistical tool that asks “What does everyone think?” It works on the basis that individual small studies may be far from conclusive, but pooling their results together can lead to stronger and more accurate results.

They looked at three strains of GM-crops that had been modified with genes from a soil-dwelling bacterium called Bacillus thuringiensis. The transferred genes are responsible for producing a number of biological (and therefore ‘natural’) insecticides. When moving them across to plants, geneticists typically try to match the insecticide to the pest they are trying to fight. (In the image on the right, Bt-peanut leaves are protected from the damaging European corn borer)Some GM crops are resistant to specific insect pests.

The toxins are delivered at high dosages to pests, but are restricted to the plant (and sometimes even to particular tissues). They can also be added to the chloroplast genome, which is quite separate form the plant’s nuclear DNA. This stops them from being transferred to other plants.

The hope is that these so-called ‘Bt crops’ can help to minimise the collateral damage of less targeted insecticide sprays. In theory, only pest insects that eat valued crops are killed, while the rest of the ecosystem is unharmed.

The results

That’s what Marvier set out to test. She looked at field experiments which tested the impact of caterpillar-resistant cotton and maize plants on the abundance of other groups of insects and invertebrates.

She found that these other creatures are found in greater numbers in fields containing the caterpillar-resistant GM plants, compared to those sprayed with conventional insecticides. However, the GM crops also led to slightly lower numbers of non-targeted insects compared to fields where no GM crops and no insecticides were used.

The results stayed the same even when Marvier analysed them in more detail. For example, she found much the same thing when she only looked at experiments that had been published in peer-reviewed scientific journals.

So assuming that Bt crops do indeed reduce the use of insecticides (and that’s far from proven), then they will also, as claimed, reduce the collateral damage caused by these chemicals. But they’re not as good for the environment as using no insecticides at all, be they engineered or sprayed.

The bigger picture

Bt-crops are better than large-scale insecticide spraying.At the local level, Marvier’s study provides some much-needed scientific backbone to the GM debate. But the real decisions need to be weighed up at a larger level. For example, it’s all well and good to say that a no-insecticide, no-GM field is the best solution, but that leaves farmers in a bit of a lurch.

One of the big criticism levelled against organic farming is that it leads to lower yield than other practices and requires more agricultural land to be viable and that deals a bad hand to farmers in the developing world. This in turn could lead to deforestation and habitat loss.

On the other hand, Marvier advises caution when interpreting her work. This study has revealed just one benefit of GM crops and even then, only for one specific type of genetic modification. Many of the studies involved isolated patches of land, rather than entire farming systems, where the situation is more subtle. Not all non-GM crops are sprayed with insecticides, while not all GM crops are free from them.

Any benefits must also be weighed against potential health or environmental risks, and again, these must be researched carefully.

To Marvier, the clearest message from her study is that we have started to accumulate enough data to look at this issue from an empirical, evidence-based point of view. If we are to make sound decisions, there is little room for anecdotal evidence or knee-jerk responses guided by personal philosophy.

Bt hypocrisy

For example, there is a certain irony to the opposition to Bt crops. Because its insecticides are ‘natural’, the bacterium is one of the few pesticides that organic farmers are allowed to spray onto their crops.

The bacteria of course use the exact same genes that are transplanted into Bt-engineered crops. Some may argue that this method is better because it is more ‘natural’, because the genes stay within the organism they were intended for. But is that really better?

Wholesale Bt spraying is a crude technique than the specific and targeted use of Bt-engineered crops. It means that the surrounding land is also covered in the bacteria and creatures other than pests are exposed to its entire gamut of toxins. And because farmers need constant supplies of the bacteria, it soaks up more money.

Reference: Marvier, McCreedy, Regetz & Kareiva. 2007. A meta-analysis of effects of Bt cotton and maize on nontarget invertebrates. Science 316: 1475-1477.

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Related stories on genetic modification:

Genetically-modified mosquitoes fight malaria by outcompeting normal ones
Magnifection: mass-producing drugs in record time
Feed the world – turning cotton into a food crop

Sneaking medicines past the brain’s defences

The brain is surrounded by a protective barrier designed to keep infections out. But it can also block out medicines intended to treat brain diseases. Now, scientists have developed a way of sneaking helpful proteins across the barrier by giving them fake molecular ID.

Using genetic engineering, a group of scientists have developed a way of sneaking a virus past the brain’s defences. Don’t panic – this isn’t some nightmare scenario. It could be the first step to curing a huge number of brain diseases.

The brain needs to be protected from incoming infections.The brain seems incredibly well protected amid its shell of bone and cushioning fluid. But even the strongest of forts needs supply lines, and brain is no exception.

A dense network of blood vessels carries vital oxygen to its cells. These vessels are a potential vulnerable spot, providing access for bacteria and other disease-causing organisms to migrate in from other body parts.

But even these weak spots are heavily guarded. The blood vessels in the brain are lined with a tightly packed layer of cells that restrict the flow of molecules from blood to brain. These cells form a protective shield called the blood-brain barrier, or BBB.

It is a superb defence but it can do its job too well. Not only does it block out dangerous microbes, but it can also exclude large proteins and drugs designed to treat brain diseases. Usually, these large molecules need to be distributed throughout the entire brain to be effective. With the BBB in the way, they don’t stand a chance.

Now, Brian Spencer and Inder Verma from the Salk Institute of Biological Studies have come up with a way to disguise helpful molecules to sneak them past the brain’s defences.

The blood brain barrier controls the import of molecules into the brain with the tight security of airport immigration.Their method exploits special gates in the barrier that control the import of essential nutrients and molecules like cholesterol into the brain. These molecules are escorted by a large protein called apoliprotein B (apoB), and are presented to sentinel proteins that guard the gates.

One of these guardians, called LDLR, is designed to recognise a specific segment of apoB. Once it has confirmed the visitor’s identity, it escorts apoB and the molecules it accompanies through the barrier. The whole system works with the tight control of a maximum security prison.

Spencer and Verma managed to fool the system. They took the part of apoB that is recognised by LDLR and stuck it to various proteins, giving them the molecular equivalent of a fake pass.

First, they tested their method in mice. They injected the animals with a harmless virus designed to travel to its liver and spleen. There, the virus sets about building the disguised protein, which is secreted en masse into the bloodstream.

The beauty of this method is that it works after a single injection that transforms the liver and spleen into factories for the protein of choice.

Spencer and Yerma’s method works for glucocerebrosidaseTheir first candidate was GFP, a jellyfish protein that glows in the dark with a greenish hue, allowing it to be easily tracked. Sure enough, the injected mice soon gave off a greenish glow from their brains and the rest of their central nervous systems.

Better still, their method showed real practical potential by sneaking an enzyme called glucocerebrosidase (right) into the brain. Glucocerebrosidase is vital for the storage of fats. People who lack it suffer form a condition called Gaucher’s disease, where fatty desposits collect on various organs and cause brain damage, among other symptoms.

The disease is relatively easy to fix using regular injections, but the resulting brain damage is not for the injected enzyme is usually repelled by the blood-brain barrier. But Spencer and Verma’s method may change all that.

The duo fully admit that their work is merely a first step, but it is an important one nonetheless. The technique must first be refined and tested in people before it can be widely used. Developing drugs and proteins for treating brain disorders is pointless if those new medicines just congregate uselessly outside the blood-brain barrier. Spencer and Verma may have given them a way in.


Reference: Spencer & Verma. 2007. Targeted delivery of proteins across the blood-brain barrier. PNAS 104: 7594-7599.

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Feed the world – turning cotton into a food crop

The world’s cottonseed harvest have enough protein to feed half a billion people in the world’s poorest places, but are inedible because they contain a potent poison. Now, scientists have found a way of removing that poison, and turning cotton into a stunning new food source.

 

Feed the world. Let them know it’s Christmas time.” The world is currently home to 6.5 billion people and over the next 50 years, this number is set to grow by 50%. With this massive planetary overcrowding, Band Aid’s plea to feed the world seems increasingly unlikely.

Current food crops seem unequal to the task, but scientists at Texas University may have developed a solution, a secret ace up our sleeves – cotton.

Cotton is infused with a potent poison called gossypol. Cotton is famed for its use in clothes-making and has been grown for this purpose for over seven millennia. We do not think of it as a potential source of food, and for good reason.

The seeds of the cotton plant are rife with a potent poison called gossypol (see below) that attacks both the heart and liver. Only the multi-chambered stomachs of cattle and other hooved animals can cope with this poison, relegating cottonseed to a role as animal feed.

Getting rid of gossypol could go a long way to reducing the world’s hunger crisis. A fifth of a cottonseed’s weight is made up of oil, and a quarter of high-quality protein. For every kilogram of fibre, each cotton plant produces 1.65 kg of seed.

And the plant is grown in over 80 countries by some 20 million farmers, the majority of whom live in the poorest parts of the world, where starvation is an ever-looming threat. If only the seeds could be made edible.

GossypolIn 1954, scientists attempted to launched a programme to cross-breed normal cotton plants with a mutant strain that lacked the glands that make gossypol. Unfortunately, they discovered that cotton creates the poison for a reason.

It infuses the plant’s various tissues, protecting it from insect pests and infections alike. The programme’s seeds were safe for human consumption, but the weakened plants readily succumbed to insect attacks, destroying their commercial potential.

Now, Ganesan Sunilkumar and colleagues have solved the problem. They have used a technique called RNA interference, or RNAi, to turn off a gene called delta-cadinene synthase, which is essential for gossypol production.

But in this case, the team put their system under the control of a genetic switch used only in cotton seeds, and not the rest of the plant. As a result, levels of gossypol plummeted in the plant’s seeds and these alone. The rest remained as strong as ever against attackers.

Sunilkumar ran their special plants through a series of tests to make sure that the RNAi’s effects never spread to the rest of the plant. They passed every one. Best of all, the altered plants stably passed on their characteristics to their daughters.

This study is testament to both the power and the precision of modern genetic technology. The researchers identified a very specific point in a biochemical pathway and blocked it in a single part of the plant. The result is a variant that retains the original’s survival abilities, but is suddenly fit for human consumption.

Their approach has tremendous potential for opening up other food sources. For example, the beans of the tropical grass pea, Lathyrus sativus, are often eating by poor people in Africa and Asia in times of dire need.

As the beans contain a potent neurotoxin – a nerve poison – those eating them often contract a neurological disease called lathyrism. With Sunilkumar’s technique, lathyrism could become a thing of the past.

For those who feel that the use of such technology is tantamount to playing God, consider this. Every year, 44 million tons of cottonseed are wasted. With this new technology, the engineered seed could provide enough protein for half a billion people every year.

Sunilkumar, Campbell, Puckhaber, Stipanovic & Rathore. 2006. PNAS 103: 18054-18059.

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Magnifection: mass-producing drugs in record time

Monoclonal antibodies are a rapidly emerging group of drugs with the potential for treating diseases from arthritis to cancer. Now, a new technique called ‘magnifection’ is set to drastically reduce the time and expense needed to make these molecules, ensuring that enough can be made to treat patients at a reasonable cost.

Developing new drugs is a very expensive process.

Imagine reading the paper to find that a new wonder drug has been created that could save your life, if only you could afford it. Alternatively, put yourself in the shoes of the authorities that must decide not to offer powerful new drugs on the NHS because they simply aren’t cost-effective enough. These situations are all too common-place and are largely a result of the extremely high costs of drug development. But recently, scientists at Icon Genetics and Bayer Bioscience have made a tremendous step toward lowering these costs for some of the most promising new treatments.

The treatments in question are called ‘monoclonal antibodies’ or ‘MAbs’, synthetic versions of the natural antibodies that our immune systems use to identify and neutralise infectious agents. MAbs are specially shaped to act like molecular gloves, sticking onto a target of choice and inactivating it by blocking interactions with other molecules.

The most famous member of this group, the breast cancer drug Herceptin, is one of a handful of currently available MAbs. But they are about to be joined by many more – over 150 MAbs are in development and the market for them is likely to exceed £10 billion.

But no matter how good these new biotechnological wunderkinds are, they will be worthless unless they reach the patients they are designed to benefit. And with the cost of treatment courses exceeding tens of thousands of pounds, that is looking unlikely. Every stage of the manufacturing process from raw materials to equipment is exorbitantly expensive and drives the inflated prices of the end product. As such, only better, cheaper and more effective production methods will enable scientists to fully realise the potential of these designer molecules.

Manufacturing monoclonal antibodies takes a lot of time and money. Currently, all MAbs are grown using mammalian cells and over the past twenty years, a variety of other hosts from insects to bacteria to yeast have been considered as replacements in the search for efficiency. But all these choices have crippling flaws, with the most significant being massively lengthened development times.

Plants, one of the many possible host options, are no exception to this. While mammalian cells take at most a year to produce a gram of antibodies, plants require at least two.

Combined with complex genetics, long life-spans, the need for land and the threat of contaminating wild stocks, plants seem to be a dead end as far as antibodies go. But Anatoli Giritch and colleagues have revived their potential in spectacular fashion.

Their technique, called ‘magnifection’ uses infectious agents like bacteria and viruses to carry the instructions for making antibodies throughout the plant’s cells, hidden under multiple layers of encryption. Each antibody is a union of different molecules and the recipes for making these separate components are encoded in two different viruses – one that usually infects tobacco and another that targets potatoes. Each virus is then split into different segments and loaded into a type of bacteria called Agrobacterium.

Once Agrobacterium infects the plant, it spreads rapidly and eventually reaches about 95% of its leaf cells. The addition of a specific enzyme then acts as a trigger, causing the bacteria to begin assembling viruses. These spread locally across neighbouring cells and begin churning out antibody components, turning the plant into a monoclonal antibody factory.

The result is MAb production on a scale completely unheard of. It took this system just two to three weeks to churn out a gram of antibodies, utterly smashing the current record of 6 months. And each kilogram of host leaves were yielding 10-100 times more raw product than any other production system.

The key to magnifection’s success lies in the choice of viruses. While many virus combinations compete with each other for a host’s resources, the tobacco mosaic virus and potato virus X seem to co-exist harmoniously. Giritch et al. believe that they use different host proteins to replicate themselves and so never draw upon the same pool of resources.

The duo are now trying to tweak the magnifection protocol to achieve even better results. They will consider different virus combinations and will try to add chaperone molecules that help antibody components to combine with greater efficiency. Regardless of any further improvements, the implications for magnifection are tremendous. The technique is rapid, versatile and can be easily scaled-up. The result will be more drugs at lower prices leading, hopefully, to a better deal for patients.

Magnifection is particularly suited to situations where we might need to manufacture vast quantities of antibodies or other complex molecules in a short amount of time. A viral pandemic, or a biological terror attack, are just two examples of such emergencies.

Giritch, Marillonnet, Engler, van Eldik, Botterman, Klimyuk & Gleba. 2006. PNAS 103: 14701-14706.