Julian Ma is joint head of the infection and immunity research centre at St George's Hospital Medical School in London. He specialises in genetically modifying plants to produce useful drugs, a process called pharming, which he hopes will bring cheaper drugs to the developing world. His Pharma-Planta project was recently given permission by the UK medical regulator, the Medicines and Healthcare products Regulatory Agency, to carry out human trials of a monoclonal antibody, grown in tobacco plants, that can be used to prevent HIV infection. How is a regular drug made?
The class of drugs we're dealing with are called recombinant proteins. What that means is a kind of protein that is made in a system that is not the host system for that original protein. Recombinant proteins have been made for decades using GM technologies – it started with GM bacterium E coli, which was used to make human insulin. Then we moved to GM yeast (an example of that is the vaccine against hepatitis B). More recently, the gold standard for making recombinant proteins, particularly monoclonal antibodies (Herceptin is a good example), is to use mammalian cells. The most commonly used one is a cell derived from the ovaries of a Chinese hamster (CHO). Those cells are grown in big fermenters as a liquid culture.
Why would using plant cells be better than these traditional methods?
These fermentation vats have to be kept absolutely sterile and the manufacturing facilities that are involved are very expensive. The thinking behind going to whole plants was: here we have a very simple and efficient protein-manufacturing system that simply uses sunlight, water and soil to make proteins. It's no coincidence that plants are at the bottom of the food chain, because it's the cheapest and most economical way of making proteins on a large scale.
How pure is the protein that comes out of your experimental plants?
There are many potential variables. The conditions under which you grow the plant inherently has some variability; daylight affects it, and there's variability of the environment around the greenhouse. And you've got soil in your greenhouse, the growth medium. What we've shown in our work is that, despite all the variations, what comes out of the plant can be made to very high quality; in fact, the quality we reached was even higher than had been previously achieved using the CHO system.
Can you use any plant for pharming?
There are some other species, such as maize, which would work very well – any plant that produces a seed would be a good target for us, because seeds are essentially dehydrated protein-storage bodies. We've chosen tobacco for several reasons: the most important is that it's not part of the food chain, and we were acutely aware that we needed to find a species that would not give us environmental issues about whether we might pass our product into the food chain. Tobacco is a major crop around the world, so, if you're looking at non-food crops, tobacco is the best-established one. And third, it produces a huge amount of biomass – if you want to create a very large-scale production system, biomass levels are important.
Where will this go in future?
One of the great areas for potential growth of plants is in making not just very complex molecules but also combinations of complex molecules, like antibodies. The product we're working on, the anti-HIV antibody, eventually will have to be used in combination with one or two antibodies: it's very unlikely it will be used by itself. The reason for that is that HIV is very good at mutating, so you need to provide two or three antibodies to prevent viral escape. That concept is applicable across the board for infectious diseases. Plants give you the option of making many molecules to add to a cocktail of pharmaceuticals, because the potential cost of making the molecules is much lower than conventional systems. You can now afford to make cocktails of two to three antibodies, whereas, up until now, we haven't been able to afford that.
Could you one day eat plants to extract the drugs, instead of processing them?
This suggestion has been around for quite a long time now and it is attractive, but there are some difficulties with that. The early suggestions of growing banana trees or tomato plants and having fresh produce as a delivery tool have been discarded, mainly because you can't control the dosage of your medicine very easily. That doesn't mean you can't take that sort of system and combine it with some simple food-processing technology. If you were able to produce a medicine in an edible fruit, like a tomato, you could do a simple food-processing step to stabilise the protein in the tomato product and also standardise the dose. That could be delivered by the oral route.
Delivering vaccines by the oral route has been the holy grail of vaccinologists for decades. There are some technical difficulties with it: some people don't respond well to oral vaccines and there are some immunological issues. But the potential is there. I think that is some way off, however, and what we've done at this stage – shown that plants are a viable manufacturing system for vaccines or antibodies – is the first step along a very long road that will ultimately lead to an edible vaccine. In the interim, this will give us many other valuable products which look much more like conventional pharmaceuticals.
Will your technique make drugs cheaper?
The real cost of pharmaceuticals is not down to the cost of the goods themselves, it's due to the many years it takes to develop a drug, and many other steps. Where I think the cost benefit does come in, though, is in the very early stages of drug development. In a plant system, the investment you have to make early on to test a new drug is much lower than if you wanted to make it by conventional systems. That could be 10- to 100-fold cheaper. We know that many drugs fail in the first few years of development, but if the cost of trialling each of those drugs is very high, very few people are able to enter the field. If you make the cost of entry into looking at new drugs much lower, using plant technologies, it allows you to bring underdeveloped countries in to look at drugs that they might find very important.
