Out of Africa
How an African herbal tea launched a revolutionary line of medicine.
Almost 30 years ago, Professor David Craik made a discovery that would change the world’s understanding of peptides, a crucial component of many modern medicines.
His finding led to the development of a whole new line of plant medicines, including a powerful new type of pain relief and the world’s first natural plant insecticide.
However, the story didn’t begin with Professor Craik. In fact, it began many years earlier in Africa, when a Norwegian anaesthetist noticed something unusual about the labours of pregnant women in the Congo.
In the 1960s, the Republic of Congo was experiencing a period of violent revolution.
The country’s joy at being granted independence from colonial Belgium quickly turned to terror as local factions began a violent fight for rule of the new country. As the casualties of war mounted, medical assistance was desperately needed.
The Red Cross answered the call for aid, flying teams of doctors into the region.
Many people were desperately in need of surgical intervention. The newly arrived surgeons' efforts were stalled, however, as there weren’t enough anaesthetists to put the patients to sleep.
Norwegian anaesthetist Lorents Gran was called in to assist, cutting short his honeymoon.
In the midst of all the mayhem and bloodshed, he noticed something unusual. The pregnant Congolese women in his hospital were going through considerably shorter labours than he had ever seen before.
Determined to find out why, Gran started documenting birthing practices in the maternity ward.
He saw the labouring women were encouraged to drink a tea brewed from a local herb known as Kalata Kalata (species name Oldenlandia affinis). Once he found this name approximately translates to ‘fast fast’, he suspected the local women might be on to something.
Gran’s investigations revealed the active ingredient in the plant was a naturally occurring peptide, which he named kalata B1.
A peptide is a chain of amino acids, like a protein, but smaller. Peptides support many functions in the body and are chemically synthesised for a wide number of medicines.
It seemed the peptide Gran had identified was causing the pregnant women’s uteruses to contract, speeding up the labour process. Mystery solved.
There was only one problem: peptides are broken down by the body when ingested, and they certainly don’t survive boiling. This is why chemically synthesised peptide drugs like insulin are injected, not eaten. So how was this peptide still effective after being made into a tea and drunk by the women?
Gran published his findings, leaving this mystery for future bioscientists to solve.
Image: Express/GettyImages
Thirty years later, and halfway across the world, Dr David Craik stumbled across the samples of Kalata Kalata plant in the Biochemistry Department at Oxford University.
These samples had been left there 10 years earlier by a Norwegian researcher who had seen Gran’s findings and tried – but failed – to determine how the plant caused its seemingly impossible effects.
Craik was a young Australian bioscientist on four months of sabbatical leave from the Victorian College of Pharmacy. Shocked by short winter days and the bitter cold, he was forced to seek refuge in his lab – but it was perhaps thanks to this confinement that he made his most famous discovery.
What he found was that the kalata B1 peptide had a circular structure. This was a shock as circular peptides had never before been documented. He named this new class of molecules 'cyclotides' (meaning circular peptides).
Most peptides aren’t formed into a closed loop, and are broken down by enzymes that eat at them from the ends inwards. Once the peptide begins to break down, its function is lost.
The circular shape of the kalata B1 peptide was what made it strong enough to survive being eaten – it had no weak ends, so didn't degrade as easily.
This discovery was a changing point in Craik’s career. But acclaim for this find was not immediately forthcoming, as he first had to deal with a sceptical scientific community.
It wasn’t just the kalata B1 peptide’s circular structure that raised eyebrows; there were other aspects of its composition that made Craik’s claims seem unbelievable.
“No one actually believed us at the time because no such thing had been seen before,” he explains.
“Because it was such an unusual structure, and people were doubting it when I talked about it at seminars, I didn’t actually publish it until five years later.”
Craik realised that to convince the world, he needed more evidence of these circular peptides occurring in nature. The kalata B1 cyclotide was still the first – and only – of its kind on record.
But was it unique?
Because the plant was from the Rubiaceae family, Craik decided to look at other species from this same line. However, with the Rubiaceae family tree containing up to 15,000 species, he had a big task ahead.
Thirty years later, and halfway across the world, Dr David Craik stumbled across the samples of Kalata Kalata plant in the Biochemistry Department at Oxford University.
These samples had been left there ten years earlier by a Norwegian researcher who had seen Gran’s findings and tried – but failed – to determine how the plant caused its seemingly impossible effects.
Craik was a young Australian bioscientist on four months of sabbatical leave from the Victorian College of Pharmacy. Shocked by short winter days and the bitter cold, he was forced to seek refuge in his lab – and it was perhaps thanks to this confinement that he made his most famous discovery.
What he found was that the kalata B1 peptide had a circular structure. This was a shock as circular peptides had never before documented. He named this new class of molecules 'cyclotides' (meaning circular peptides).
Most peptides aren’t formed into a closed loop, and are broken down by enzymes that eat at them from the ends inwards. Once the peptide begins to break down, its function is lost.
The circular shape of the kalata B1 peptide was what made it strong enough to survive being eaten – it had no weak ends, so didn't degrade as easily.
This discovery was a changing point in Craik’s career. But acclaim for this find was not immediately forthcoming, as he first had to deal with a sceptical scientific community.
It wasn’t just the kalata B1 peptide’s circular structure that raised eyebrows; there were other aspects of its composition that made Craik’s claims seem unbelievable.
“No one actually believed us at the time because no such thing had been seen before,” he explains.
“Because it was such an unusual structure, and people were doubting it when I talked about it at seminars, I didn’t actually publish it until five years later.”
Craik realised that to convince the world, he needed more evidence of these circular peptides occurring in nature. The kalata B1 cyclotide was still the first – and only – of its kind on record.
But was it unique?
Because the plant was from the Rubiaceae family, Craik decided to look at other species from this same line. However, with the Rubiaceae family tree containing up to 15,000 species, he had a big task ahead.
At the same time, Craik was preparing to return to Australia. Originally from Victoria, he was drawn to UQ thanks to a big drive by the University and the state government to make Queensland the national centre for biotechnology.
After settling into a new home at Chapel Hill in Brisbane in 1995, Craik realised his search might start much closer to home than he had imagined. Growing in his own backyard were two of the most famous species from the Rubiaceae family – coffee and gardenia plants.
While he didn’t find cyclotides in either the coffee or gardenia leaves, he wasn’t deterred.
His search soon found a new and important direction after he came across an obscure academic paper from Austria. The researchers had found circular molecules in plants from the violet (Violaceae) family, although they had not been able to fully determine the structure.
In light of this clue, Craik turned his garden shears on the native violets in his garden. He was shocked to find not just one but 50 or 60 different types of cyclotides within this single plant.
The mission to find other naturally occurring peptides would launch Craik onto a worldwide search that would eventually take him from the rainforests of Far North Queensland and the deserts of Central Australia, to the mountains of Thailand and the jungles of Vietnam.
Today, hundreds of natural cyclotides have been discovered, in around 50 different plants – work driven largely by researchers at Craik’s UQ laboratory.
Image: StudioOne-One/GettyImages
While realising cyclotides might be all around us, Craik also saw they were definitely not a common feature of all plants.
“The big puzzle from an evolutionary perspective is why some plants have cyclotides and others don’t,” he says.
“Even two plants, that are seemingly close to each other taxonomically, don’t necessarily have the same repertoire of cyclotides.”
To answer this question, Craik and his team, alongside collaborator Professor Marilyn Anderson from La Trobe University, started trying to uncover what the actual function of cyclotides might be for their plant hosts. Experiments with some cyclotides extracted from several plant families showed that these molecules seemed to have dramatic insecticide properties.
This discovery led to the development of the world’s first natural plant insecticide.
Humans also need protection from pests and pathogens, so Craik started work developing cyclotides for use in antimicrobial and antifungal medicines. His vision for the future was that rather than laboriously synthesising peptide drugs in the lab, we should make the most of what already surrounds us in nature.
What potential medical marvels might be quietly photosynthesising in your yard? Bronwyn Smithies, a doctoral student in Professor Craik’s lab, explains:
Naturally occurring plant peptides provided a wealth of leads for drug discovery. But Craik’s lab started looking at what the animal world might have to offer.
They had the idea to chemically remove a section of a plant cyclotide and replace it with a peptide taken from the venom of a cone snail, known to have strong pain killing properties. The venom was very useful for extreme pain relief (for example, in surgery), but could only be administered by spinal injection.
A highly venomous cone snail. Image: Auscape/Getty Images.
A highly venomous cone snail. Image: Auscape/Getty Images.
By chemically grafting the venom into a cyclotide, it could now be taken orally. Craik’s lab had just produced the world’s first natural oral pain relief that uses animal venom. This drug could have pain-relieving effects 100–150 times more potent than the current market leader (Gabapentin).
While animal venom research often gets a lot of attention because, let’s face it, animal venoms are exciting, Craik argues we should be more impressed by peptide plant defences.
“If you’re an animal and you get attacked by a predator, you can either run away or fight. But if you’re a plant, you can’t do that, so you have to have a really good peptide- or protein-based defence,” he says.
“Because they have to be so good at this, I think there should be more interesting peptides and proteins in plants than in animals, just waiting to be discovered.”
As new drugs are discovered and developed based on his ground-breaking discovery, Craik and his team are working on a new vision for the future of drugs – edible plant medicines that you can grow in your own backyard.
From sunflower seeds to cure prostate cancer, to French Fries for obesity, Craik hopes to cut the costs associated with big pharma drug development, and open accessibility to medicines for people in the developing world.
“I’ve done a fair amount of fieldwork in Africa, and the life expectancy there is only 47–55 because of HIV/ AIDS. It’s not because there aren’t good drugs for it; there are perfectly good drugs. But they just can’t afford them when we design them conventionally,” Craik explains.
“If they could grow anti-HIV drugs in their backyard plants, then maybe we could have an impact there."
“The same for malaria – it kills 400,000 people a year, and there is resistance to existing drugs. If we could get a peptide-based medicine for malaria that could be grown in plants in Africa or India, for example, that could really be a gamechanger worldwide.”
Craik and his team have a wide range of drug leads in biochemical development, and several in animal trials.
With the announcement of $35 million in funding to open the ARC Centre of Excellence for Innovations in Peptide and Protein Science, Craik is confident their cyclotide medicines could move to human trials within the next 5–10 years.
Watch a video below about Professor Craik's medicines in plants research and how we are encouraging support for this game-changing research.
Professor David Craik
ARC Laureate Fellow - Group Leader
Institute for Molecular Bioscience
Affiliated Professor
School of Biomedical Sciences
Faculty of Medicine
Words by Harriet Dempsey-Jones
Image credits: Header image – AFP/GettyImages; Oldenlandia affinis & Kalata-B1 structure – Bronwyn Smithies; Flowers 1-4 – Bronwyn Smithies; Sunflower – Brian Hagiwara/GettyImages.
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