The cost of pharmaceuticals is rising. For an economically developed country such as Australia, these increasing costs place a growing demand on an already spiralling health expenditure. For a developing country, these costs make many drugs simply unattainable.
Although there is no single, straightforward solution, left-of-field ideas that challenge the typical paradigms of big pharma provide some hope. One such idea comes from David Craik from the University of Queensland and Marilyn Anderson from LaTrobe University.
This month Craik and Anderson received the biennial Ramaciotti Biomedical Research Award to develop plants as “biofactories” – essentially genetically reprogramming something biological (such as a plant or microbe) to do industrial-scale grunt work – to produce a class of compounds called cyclotides.
As a long-term goal, this project offers the tantalising possibility that plants containing otherwise unaffordable drugs, such as agents to treat HIV, could be farmed on a small scale at low cost by communities that need them most. Active drugs could be obtained by a process as simple as making tea.
What are cyclotides?
Cyclotides are a class of mini proteins obtained from certain species of plants.
Their scientific discovery was serendipitous – a Red Cross relief worker in the Democratic Republic of Congo in the 1960s noticed that women of the region used a tea made from the leaves of Oldenlandia affinis to induce labour.
Using plants for medicinal properties is as old as civilisation. The surprising finding was that the active principle, later called kalata B1 (after the local name for the plant kalata kalata), was a peptide, or small protein.
Peptides and their larger cousins, proteins, are made from chains of amino acid building blocks.
Although many larger proteins are being used successfully as drugs – indeed, proteins are currently the fastest growing class of new therapeutic compounds – smaller proteins and peptides are generally not well suited for use as drugs. They often lack the self-supporting structure of larger proteins. As a consequence, they’re readily broken down into their amino acid building blocks in the blood, so their effects don’t last long.
The gut is an even more hostile environment for peptides. Even large proteins are readily broken down to amino acids before they can be absorbed. As a result, when they are used as drugs, peptides and proteins typically must be given by injection.
Cyclotides, though, have unusual structural features. They’re tightly folded and compact, stabilised by three strong chemical bonds between sulphur-containing amino acids. This forms a so-called cystine knot structure.
Cyclotides have a further feather in their cap. The plants that make them contain an enzyme that joins together the two ends of the peptide chain – cyclotides are circular.
In most other peptides and proteins, the free ends act as sites where enzymes can begin to nibble away at the amino acid chain. In the circular cyclotides, there are no ends. So the process of breaking down the amino acids is much more difficult.
These features give the cyclotides their thermal stability, allowing them to survive the kalata kalata tea-making process. It also gives them sufficient stability in the gut to make them active after oral administration, a property almost unique in the peptide and protein world.
How can plants be used as biofactories?
Craik’s group has led the world in showing how you could use the stable cyclotide structure as a support to incorporate new sequences of amino acids that could have entirely new biological effects. Using this approach, it has been possible, for example, to create modified cyclotides that have anti-HIV actions, as well as agents directed at other infectious diseases, cancer and heart disease.
Together with Anderson, Craik will now examine ways of coaxing plants to produce these modified cyclotides in high enough levels to render them an economically viable, sustainable source of drug.
Using plants as biofactories for drugs is not a new idea. Travel to Tasmania and you will see large fields of opium poppies, protected by barbed wire and electric fences, licensed to a multinational pharmaceutical company for the production of morphine. Although the raw material is agricultural, its production is large scale, and the final manufacturing of drug is high tech and multinational.
What Craik and Anderson are proposing is an approach to drug production at a community level. In regions where there is a pressing need for drug therapy that cannot be met, for whatever means, by big pharma, small scale-plant cultivation and simple low-cost extraction procedures offers a potential solution.
In sub-Saharan Africa, where there is a dramatic and urgent need for affordable treatments for HIV, growing-and-brewing-your-own anti-HIV drug would be a fittingly circular journey for cyclotides back to Africa.
This sort of science is risky, and can be difficult to get funded. Government funding organisations often view this as work pharmaceutical development, the realm of big pharma. For big pharma though, it is far too uncertain, and sits well outside that industry’s expected and trusted paradigms.
In the current climate, it is philanthropic bodies that are most likely to have the patience, as well as the desire and ability to take a punt, that is required to nurture potentially game-changing projects such as these.