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Pharming. Growing medical drugs

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Location: Verde Valley, AZ.
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this is behind a log in wall, but not a paywall. New Scientist


there was another guy who did this for cavities in the 80's, but it was a bacterial replacement. It changed out the bacteria in the mouth, for bacteria that didn't convert sugar to acids.
result: no caries from food.
There is also ways to get mushrooms to do this, and it is a LOT quicker than using plants


The dream of getting plants to make drugs to order is finally becoming reality – but not in the way most people expected

"MY BACKGROUND is that I'm a dentist," says Julian Ma. In the late 1980s, though, he helped to invent something with the potential to put many dentists out of business: a way of eliminating the bacteria that cause cavities, while leaving the rest of the mouth's flora alone. So why do we still live in fear of the dentist's drill?

Ma's antidote to tooth decay consists of antibodies that stop the harmful bacteria sticking to our teeth. But antibodies can be made only by living cells. Without a way to mass produce antibodies cheaply, his antidote was a non-starter. Back in 1990, however, just as Ma finished his doctorate, a solution seemed to present itself. A team in California managed to get a plant to produce antibodies. Ma made a call and soon he was on a plane to California. "That was serendipity, but it came out of a need to start producing something that would be used like toothpaste by millions, billions of people," Ma says.

He found himself participating in the birth of a new science: pharmaceutical farming, or "pharming". It began with big dreams. The flagship hope was the edible vaccine, which was meant to save millions of lives in poor countries by making innoculation as simple as eating fruit.

By making sophisticated medicines dirt cheap, pharming was going to open new doors. "How about, even, like, washing yourself in an antibody against Staph aureus?" Ma suggests. "You can start to wonder about where you could use antibodies in new situations. They could replace antibiotics completely."

We are not there yet, of course. But the pharming revolution is finally getting under way. Last month, for the first time, a plant-produced protein drug was approved in the US, and many more are in the pipeline. The revolution is not happening in quite in the way the pioneers envisaged, though.

Part of the reason why pharming has been so slow to take off is technological. Lots of medicines are already extracted from plants, of course, but these are usually small molecules naturally produced in large quantities. Getting plants to make foreign proteins such as antibodies requires genetic engineering, which is a slow, hit-and-miss process. First you have to add the required genes to cells, then grow plants from them, which takes months.

At this stage, you might discover that none of the plants produce enough of the desired protein, or that the protein does not have the desired effect. Even if all goes well, you still have to generate true-breeding lines for large-scale production. "This can often take several years," says George Lomonossoff at the John Innes Centre in Norwich, UK.

Because of these issues, many of the first would-be pharmers chose to engineer food plants such as maize, even though they were not aiming to create edible products. Food plants are much easier to work with because there is so much knowledge and experience to draw on. This decision, though, made it harder to get permission to grow the modified plants in open fields. Members of the public were understandably nervous about their food being contaminated, and many scientists agreed that only non-food crops should be used to produce drugs.

In the US, this issue came to a head in 2002. The previous year, in a field in Nebraska, a farmer had grown corn modified to produce an unnamed substance for a company called ProdiGene. In 2002, when the farmer planted soya beans for food production, leftover maize seeds sprouted and were discovered growing among the soya. The resulting controversy had major repercussions. It led to an abrupt end to ProdiGene's projects and a tightening of the rules for growing pharma crops in the open. Many companies abandoned the idea of pharming in open fields altogether.

Getting permission to pharm outdoors is relatively easy compared with the next stage, though: carrying out clinical trials to prove that a product is safe and effective. Drug approval is a slow and very expensive process, and it is even more difficult when the drug in question has been produced in a new way.

One worry, for instance, is that a protein produced in a plant cell is not necessarily the same as an animal version with an identical sequence. Cells tack sugars onto proteins, and plant cells don't always add the same sugars as animal cells. This means some plant-grown proteins can trigger an immune reaction if they are injected into a person's bloodstream. To get around the issue, some groups are modifying plants to add the same sugars as animals, but this will take time.

With so many hurdles, it is hardly surprising that progress has been so slow. Ma, now at St George's, University of London, did manage to create a tobacco plant capable of producing his tooth-decay antibodies, but more than 20 years later, the commercial version of the technology - CaroRx - has yet to be launched despite successful small trials. In fact, until last month no plant-grown drug had been given the green light from the US Food and Drug Administration (FDA), although a few plant-grown products are being used commercially.

One is being made in Cuba, whose Centre for Genetic Engineering and Biotechnology in Havana created a pioneering vaccine against hepatitis B, Heberbiovac-HB, which has been exported to more than 30 other countries. The active ingredient is purified using an antibody, which used to be made by immunising mice against hepatitis B and extracting the antibody-producing cells.

In 2006, the centre started using a plant-made antibody to purify the hepatitis vaccine. The "plantibody" is extracted from modified tobacco plants grown in an indoor, soil-free system. The advance has reportedly reduced costs and boosted production of the vaccine - and spared the lives of thousands of mice.

Another pioneer is Ventria Bioscience of Fort Collins, California, which is growing rice that produces proteins such as lactoferrin, found in milk, tears and saliva. It helps protect against infections and, unlike most pharm products, it is already common in most people's diets. That means there should be no risk even if contamination occurred. Even so, Ventria is allowed to grow its rice only in sites far from normal rice fields. The company is already selling human lactoferrin for adding to formula milk for infants. It also hopes to get its lactoferrin approved as a treatment for preventing diarrhoea in vulnerable patients put on antibiotics. It is, however, just about the only company pharming in open fields.

Most other groups are taking a different approach, largely thanks to advances in technology. One is the development of ways of growing plant cells, rather than whole plants, in big vats, in a similar way to production using animal cells. Large quantities of cellscan be grown faster than entire plants. The big advantage of using plant cells rather than animal cells is that there is no risk of the cells being infected by mammalian viruses that could infect people too.

And because the cells are grown in sealed chambers and no seeds or pollen are ever produced, there is no risk of the added genes getting into any agricultural or wild strain of plant. This means companies do not need the kind of approval required to grow genetically modified plants in open fields.

"We have the best of both worlds," says David Aviezer, head of Protalix Biotherapeutics in Carmiel, Israel, the leading company in this field. "Because we use cells, not field-grown plants, we don't come under the same rules." Using plant cell cultures is more about ensuring that the end-product is pure than preventing genetically modified material contaminating the environment or the food chain, he says, but it achieves both.

The company's first product is a treatment for Gaucher's disease, a rare genetic condition in which an enzyme deficiency causes a fatty build-up in vital organs. Protalix is producing a synthetic version of this enzyme, called taliglucerase alfa, in modified carrot cells grown in huge, disposable plastic sacks. The only thing carrot-like about the process is the colour of the culture (pictured). On 1 May, taliglucerase alfa became the first genetically engineered protein produced by plants to receive full approval by the FDA.

The plant-grown enzyme will be competing with another version of the missing enzyme, called imiglucerase, which is produced using vats of Chinese hamster ovary cells by a firm called Genzyme at a factory in Allston, Massachusetts. It is one of the most expensive drugs ever, costing $200,000 per patient per year - and it needs to be taken for life. Worse still, Genzyme had to temporarily shut down production in 2009 because of viral contamination, leading to shortages.

The prospect of producing drugs more cheaply and safely in vats of plant cells has got big pharma interested. Drug giant Pfizer has licensed Protalix's technology, so taliglucerase alfa could be the first of many drugs grown this way. It is still a far cry from the dream of producing drugs very cheaply, though. At something like $150,000 a year, taliglucerase alfa will be cheaper, but it could hardly be described as cheap.

A shortcut to making proteins in plants could help bring that vision closer. Instead of spending months or years creating genetically engineered plants, the idea is to add DNA coding for the desired protein to the leaves of normal plants. This is usually done by infiltrating the leaves of tobacco plants with a solution containing a bacterium called Agrobacterium, which can get pieces of DNA inside plant cells. Then all you have to do is wait a week or two for the leaves to produce the protein and harvest the leaves. This method is known as transient expression, because protein production would gradually stop after a few weeks (see diagram). The added DNA rarely gets incorporated into the genomes of cells and instead slowly breaks down.

Although transient expression offers an enormous advantage in terms of speed, it has never been practical commercially because very little protein is produced. Researchers have tried all kinds of tricks to boost protein expression, such as introducing RNAs that replicate themselves in a similar manner to viruses, with little success.

This is where Lomonossoff comes in. He discovered that a plant virus, the cowpea mosaic virus, has sequences flanking its genes that hugely increase protein expression (Plant Physiology, vol 148, p 1212). Add another sequence that disables a plant's in-built defences against foreign RNA and it is possible to get more than a gram of the desired protein per kilogram of plant weight - which is a lot.

His team's "hyper translatable" system can be used on a small scale to speed up research, by producing a few milligrams of a protein at a time. It is also being scaled up for producing kilograms by companies such as Medicago of Quebec, Canada. It has sealed greenhouses full of tobacco plants, and has developed an automated system for infiltrating these plants with the desired DNA. It is using the technology to make flu vaccines. Its vaccines consist of an empty shell - a virus-like particle - embedded with the surface proteins of the relevant flu virus.

Flu vaccines are normally produced using chicken eggs, and with eggs it takes several months to produce a vaccine to a new flu virus. Medicago has proved that it can do it just three weeks after getting the sequence of the new virus (PLoS One, vol 5, p e15559). "We download a flu's genetic sequence from the internet and use it to make a DNA fragment which we clone into Agrobacterium," says Andy Sheldon, head of Medicago.
Running the numbers

Medicago is being paid by the US military to develop and test ways of producing vaccines rapidly in case, say, H5N1 bird flu starts spreading between humans. It has built a facility in North Carolina capable of producing 10 million doses a month. Sheldon claims the plant-based method is not only faster, but 10 to 20 times cheaper than conventional ways of making flu vaccines, so it might one day be used for producing normal seasonal flu vaccines - and perhaps many other kinds of proteins, too. Medicago has "run the numbers" on the production of antibodies, and Sheldon thinks greenhouse production would be cost effective. So is there any need for pharming in open fields at all?

Yes, says Ma. He has been leading a project, run by the Pharma-Planta research consortium, to produce anti-HIV antibodies in tobacco, one of which was successfully tested in a clinical trial last year. Only open field growing would allow a cocktail of antibodies to be produced cheaply enough to combat HIV in sub-Saharan Africa, he says. Building greenhouses is too expensive. The same is true for non-pharmaceutical products such as industrial enzymes, which usually need to be dirt cheap to compete in the market.

For high-value products for rich countries, though, sealed greenhouses could be the way forward. "Greenhouse technology is amazing now," says Ma. "In Holland or southern Spain they look like cities, they're huge."

So pharming is finally becoming a reality, but it looks as though it will mostly take place behind closed doors rather than in open fields. Unfortunately, if the price tag for taliglucerase alfa is anything to go by, it may be a few years yet before we start washing with antibodies or brushing our teeth with them.

Hal Hodson is a science journalist based in London.
Issue 2867 of New Scientist magazine

* From issue 2867 of New Scientist magazine, page 40-43.

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