Green drug factories
Every year hundreds of millions of people are struck down by this parasitic disease and more than half a million - the majority of them young children - die from it. There's one very effective class of drugs that can successfully treat malaria, but they're in extremely short supply. Which is why Ralph Bock and his team have devised an ingenious way to turn tobacco plants into drug factories. Chris Smith asked Ralph about how this works...
Ralph - This compound is called artemisinin. It is produced by a wild plant called Artemisia annua. This plant makes it in very low amounts and this plant is not easy to grow. We tried to take the pathway out of this wild plant and put it into a high biomass crop which was the tobacco plant.
Chris - Do we understand the pathway by which the sweet wormwood - the plant that naturally makes artemisinin - actually makes it?
Ralph - We know the key enzymes. There are additional proteins involved in regulating the pathway. This regulation is not so well understood. That was a reason why we played a lot with different amounts of this additional proteins that are involved in controlling how much is made at the individual steps in the reaction cascade.
Chris - How much is made since you raise that point and why does the plant - the sweet wormwood plant - make it in the first place?
Ralph - It is actually not really clear why the wild plant is making this compound. Many of these metabolites in plants are made for defence reasons. Against insects, pathogens like viruses and bacteria, but in this particular case, we don't really know.
Chris - Is it expressed universally through the plant or is it expressed only in small restricted areas?
Ralph - Now unfortunately, the wild plant makes it in the so-called trichomes. These are little hairs at the surface of the leaf. This is one of the reasons why the amounts that are naturally produced in the plant are rather low.
Chris - So therefore, you've got two problems to solve. One is not just getting this into a cropping plant but also, getting it to be expressed in sufficient quantities in that plant.
Ralph - Exactly. That was the goal of our project. We wanted to take the pathway, put it into a high biomass crop and try to have it expressed uniformly in the entire plant.
Chris - What was your approach? Just literally get the genes out of the genome of the wormwood plant and put them into tobacco.
Ralph - We took a two-pronged approach. The structure that we targeted where we wanted to implement the pathway is the chloroplast. The chloroplast is the structure within the plant cell where photosynthesis occurs. So photosynthesis is the process in which the plant converts light energy into chemical energy. Putting biochemical pathways into the chloroplast has certain advantages over putting it elsewhere in the cell. One advantage is that there are many chloroplasts in the cell and many copies of the chloroplast genome of the genetic information of the chloroplast in each of these chloroplasts. This has the advantage that the amount of protein product that is made from a gene is usually much greater when we put the gene into the chloroplast genome compared to the nuclear genome.
Chris - How much artemisinin comes out from one of these transgenic plants now, compared with the parent sweet wormwood?
Ralph - The compound we are making is not exactly artemisinin. It is the immediate precursor of artemisinin called artemisinic acid which however can be converted into artemisinin by a relatively simple chemical reaction. In the amount that we've reached so far in our best producing plants is approximately 120 milligrams per kilogram. It's probably not yet sufficient for large scale commercial production but we think there is room for further improvement.
Chris - But haven't other people previously expressed the same families of genes in yeast and therefore been able to make this artificially just in yeast and then you don't have that problem.
Ralph - That's correct. It can be produced in yeast, the same compound - artemisinic acid. However, yeast production has the disadvantage of requiring expensive production sites where these yeast cells can be cultivated. The advantage of making it in plant is that plants just need water and sunlight to grow. So potentially, production in plants is much cheaper than production in bacteria or induced cells.