The day could soon come when patients could be taking their heart medication as a sprinkling of seeds on cereal or treating cancer with a daily cup of herbal tea. This is not woo being peddled by an alternative medicine salesman—it is the aim of a pair of biochemists who want to provide the next generation of drugs, for everything from HIV to chronic pain, to the world’s poor by producing them in fields using genetically modified (GM) plants instead of in factories.
Biochemists David Craik at The University of Queensland and Marilyn Anderson at La Trobe University have received Australia’s Ramaciotti Biomedical Research Award worth some $700,000 to develop the technology to turn plants into cheap biofactories for drugs made of mini proteins called cyclotides.
Like other proteins, cyclotides comprise a string of amino acids, the body’s building blocks. Unlike most proteins, though, the ends of a cyclotide are joined together so the molecule forms a circle. Cross-linking disulfide bonds reinforce the protein’s structure. It is this structure that helps cyclotides combine the best features of small-molecule drugs like Paracetamol (acetaminophen) and larger peptide, or protein, drugs like insulin.
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Because of their complexity peptide drugs are more precisely targeted and cause fewer side effects than small-molecule drugs, but the same complexity makes them more difficult to store and administer. Unlike small-molecule drugs peptide compounds normally have to be injected, because if swallowed, they are broken down into amino acids just like any other ingested protein, long before they can be absorbed and transported to their target. Without the weak point of loose ends cyclotides can resist degradation by our digestive enzymes, allowing them to reach their targets intact. "We think peptides are the future of drugs for reasons of being more selective, more potent and potentially safer, because when a peptide eventually breaks down it just breaks down into amino acids, and amino acids are food basically," Craik says.
Cyclotides were first discovered in the 1960s when Red Cross doctor Lorents Gran noticed that women in the Congo drank tea made from a local weed to speed up childbirth. The peptide kalata B1 was quickly identified as the active ingredient, but scientists could not work out why the molecule retained its activity after being boiled and drunk until Craik and his colleagues discovered its cyclized structure in 1995.
Since then hundreds of cyclotides have been found in plants around the world, and Craik believes there may be as many as 50,000. Agricultural scientists have already put some of these discoveries to use by genetically modifying cotton to express kalata B1, which Craik and Anderson discoveredalso has strong insecticidal properties that protects the crop from caterpillars without using pesticide sprays.
Scientists are not limited to natural cyclotides though; Craik has also developed a chemical reaction technique to join the ends of naturally linear peptides, giving them the same resistant properties. He has used the technique to cyclize a peptide from the venom of the cone snail to make a painkiller that is 120 times more potent than the currently used drug gabapentin in rat trials.
To produce enough of the peptides for human trials, Craik turned to his collaborator Anderson’s expertise in genetic modification technology to create plants that do the work for them, avoiding the chemical wastes generated by laboratory synthesis. Bolstered by Ramaciotti Award funding, however, the researchers are aiming even higher by engineering plants that will produce controlled doses of drugs in edible or drinkable form, even when grown in a remote village’s community garden.
The idea is not so far-fetched. Techniques are well established for genetically modifying plants, using the soil bacterium Agrobacterium tumefaciens to transfer the DNA, to produce large amounts of protein—even antibodies against Ebola are produced in GM tobacco. Scientists routinely build the gene construct with promotors that only switch on the gene in the parts of the plant where they want it to, making it easy to target drug production to the seeds, tubers or other designated parts of the plant. By targeting expression of the drugs to edible parts of the plant, Craik and Anderson hope to avoid the need to extract the cyclotides; if it does become necessary, the plants can simply be boiled to deactivate the other proteins.
The main technical challenge now is to get the GM plants to reliably express a consistent dose of the drugs so that users are not under- or overdosed. Initially, the team plans to select plants producing a high enough level of drug and to clone these plants for further study in greenhouses to determine the best conditions. The controlled growing environment of a greenhouse should allow growers to get a precise dose from their plants, but the project also aims to develop cheap kits to test the amount of any drugs produced in the field, such as dipsticks coated with antibodies to the drug. “This is relatively easy for proteins,” Craik says.
Another important hurdle is to overcome fears about the safety of GM plants and food. “We will work with the community to explain and demonstrate why our plants will be safe,” Craik says, pointing out the weight of evidence in favor of GM technology. “At least three billion meals derived from GM plants have been eaten by people and animals in 29 countries over 15 years without a single substantiated case of harm.” The plants will also only be released to the public once the drugs they produce have been accepted by regulatory bodies like the U.S. Food and Drug Administration.
Although Craik and Anderson are hopeful that pharmaceutical companies and governments will help develop the work, with inexpensive and environmentally gentle production systems a major selling point, they aim to make their medicine plants as user-friendly as possible for poor communities around the world. “We really think this could have major advantages for the developing world,” Craik told the Australian Broadcasting Corp. “The life expectancy of a male in Tanzania today is 37 years, and that's because of HIV AIDS—and that's not because we don't have good medicines for that. It's just that they can't afford it over there. But if we could be, for example, putting an anti-HIV medicine into a plant that they could be growing in their backyard, making a tea from the plant, in theory it could be something that could revolutionize the treatment of HIV.”
T. J. Higgins, a scientist at CSIRO (Commonwealth Scientific and Industrial Research Organization) in Australia who has used similar technology to develop a pest-resistant cowpea for subsistence farmers in sub-Saharan communities, believes the time is right for projects like Craik and Anderson’s. “Based on our experience developing a GM cowpea…the community is ready for a GM product that contributes to their health, provided it has passed all the safety requirements,” Higgins says.