East Cape mānuka trees produce high-quality oil that scientists hope can effectively treat school sores and tackle the looming crisis of antibiotic resistance. The region's economy could be set for a bonanza. By Peter Griffin.
It was in the steamy climate of Jakarta that Suki Harding really came to appreciate the power of essential oils.
As New Zealand's trade commissioner to Indonesia in the mid-1990s, Harding spent her days shuttling around the city helping broker deals between our exporters and local companies. But the constant humidity played havoc with her skin.
"I was relying on Blackmores tea tree oil facial wash to keep my skin in good condition," says Harding, who completed her doctorate in chemistry at Victoria University of Wellington before starting at the Department of Scientific and Industrial Research (DSIR) as a research scientist in 1988.
After an extensive career helping commercialise research either for government agencies or science-based start-ups, Harding joined Manuka Bioscience as a director and head of research & development in 2019.
The Auckland-based company sells mānuka oil-based cosmetics and personal-care treatments under the ManukaRx brand, using oil harvested from mānuka trees on the East Cape.
From lavender to jasmine and peppermint to eucalyptus, oils have been extracted from plants and used in medicinal remedies for centuries. Essential oils today are associated with a booming wellness industry that too often undermines its own credibility with overhyped New Age treatments, often served with a dose of pseudoscience. But extensive laboratory studies have confirmed the antimicrobial, antibacterial and antifungal properties of numerous essential oils. Mānuka oil alone has been the subject of more than 1000 peer-reviewed research papers over the past 20 or so years.
The ManukaRx range is popular and Harding says Manuka Bioscience has 23,000 customers across New Zealand and Australia and has just refreshed its branding as it eyes other markets. But her focus since joining the company has been on developing medical therapeutics based on mānuka oil that could be used to treat skin ailments and infections as a natural alternative to the standard antibiotics we have come to rely on – often to our detriment.
A sore point
Manuka Bioscience and the Medical Research Institute of New Zealand this month kicked off a phase II randomised clinical trial that will recruit 50 children from around the country aged between two and 14 who suffer from impetigo, also known as school sores.
The bacterial skin infection appears on the faces of thousands of school kids each year as crusty-looking golden and inflamed sores that can spread to other parts of the body.
Impetigo is contagious and disproportionately affects Māori and Pacific Island communities. In Australia, nearly half of Aboriginal children live with school sores, which can cause much more serious and invasive ailments if left untreated. Worldwide, about 165 million people suffer from impetigo at any one time.
The irony of a mānuka oil-based treatment holding promise for tackling impetigo isn't lost on any of the scientists involved in the clinical trial. The Tairāwhiti (Gisborne) region has the highest incidence of serious skin infections in children in the country.
The appearance of school scores is correlated with overcrowded housing, undernourishment and low socio-economic status. The 2018 census showed the median income for the East Cape region to be well below the national average of $31,800, with unemployment running at twice the national rate.
School sores are more than just an unsightly annoyance. Left untreated, the skin infections can spread to the lymph nodes and bloodstream, causing more serious and life-threatening illnesses.
If clinical trials of mānuka-oil formulations back up the earlier lab work, East Cape communities could become part of an expanded oil-production industry that employs hundreds of people, pumps money into the regional economy and produces what is needed to combat the disease plaguing local kids.
Antibiotic skin creams are generally used to clear up the infection, but they aren't as effective as they once were. Our reliance on a narrow range of antibiotics to treat a wide range of ailments has seen the rise of antibiotic resistance, where the targeted bacteria begin to change in response to the drug they encounter.
Some bacteria develop antibiotic resistance through mutations in their genes, and sometimes they acquire resistance by gene transfer from other bacteria. Without the resistant genes, bacteria are killed or stop growing. But the resistant ones thrive and can be passed on from human to human, from farm animals and even through the food chain and environment.
The World Health Organisation has warned that a "post-antibiotic era – in which common infections and minor injuries can kill – far from being an apocalyptic fantasy, is a real possibility". The international body estimates that by 2050, 10 million people could be dying globally each year as a result of antibiotic-resistant infections – 22,000 in Oceania alone – far outstripping the death toll of the pandemic we've lived with for the past 15 months.
"When it comes to antibiotics, some people don't use enough, some use too much. Some oral and intravenous formulations of the antibiotics have also stopped working," says Harding.
"If bugs are resistant to one antibiotic, there's a good chance they will be to others, too. It becomes a cascading problem."
We've joined other countries in profligate use of antibiotics, which is coming back to haunt us. "High levels of use of topical antibiotic creams in New Zealand have resulted in high levels of resistance," the Royal Society Te Apārangi pointed out in its 2017 report on antimicrobial resistance. "Approximately 95% of the antibiotics intended for human consumption are dispensed by community pharmacies. Sometimes these prescriptions are of nil or trivial benefit."
Our use of antibiotics in agriculture is relatively low thanks to our reliance on pasture-based farming. Other countries rely heavily on antibiotics to prevent disease, but also as a growth agent in animals. That has helped create a reservoir of antibiotic resistance in farm animals that scientists suggest is contributing to resistant bacteria in humans, too.
Superbug outbreaks such as methicillin-resistant Staphylococcus aureus (MRSA) can cause blood infections and pneumonia and have been responsible for entire hospital wards being shut down.
Governments, including our own, have developed strategies to deal with antimicrobial resistance, which chiefly rely on more prudent use of the antibiotics we already have. But we also need new types of antimicrobial treatments. New antibiotics are few and far between. "There's not a lot of money in it and there are a lot of high-cost regulatory hurdles to get over," Harding says. "For that reason, there's not been much effort put into the area of new antibiotics development by the major pharmaceutical companies."
Could mānuka oil act as a viable alternative? In laboratory experiments funded by government agency Callaghan Innovation, which is also supporting the impetigo trial, Harding has observed some remarkable results. "We tested the mānuka-oil formulations against 18 types of bacteria that cause skin infections, including MRSA and acne-causing bacteria," she says.
The lab experiments found Manuka Bioscience's mānuka-oil formulations to be 3000 times more effective than tea tree oil against bacteria that cause skin infections and more than 5000 times more powerful than mānuka honey.
"Even our scientists were surprised by the results," says Harding. "A lot of things kill Staphylococcus aureus, the bacteria that cause impetigo, but not many things kill the antibiotic-resistant staph bacteria, so that was pretty awesome."
What makes mānuka oil so powerful? "Its unique bioactive properties," says Harding. Mānuka oil has a unique chemical identity or "chemotype" called the high triketone chemotype. "Triketones are special chemicals that are responsible for the powerful antimicrobial properties of East Cape mānuka oil."
The properties are a product of the East Cape's microclimate and act as a sort of sunscreen to protect the mānuka trees. "They've evolved over time to develop these plant sunscreen chemicals that also have hugely beneficial human therapeutic properties."
How exactly essential oils fight the bacteria that cause infection depends on their complex chemical make-up. Some oils are particularly effective against so-called gram-positive bacteria, which can cause impetigo, blood poisoning, surgical wound infections and even flesh-eating bacterial diseases.
Gram-positive bacteria have a simple cell wall and lack an outer membrane. This makes the cells highly permeable to the molecules of antibiotics and essential oils. Some oil compounds attack the cell walls and others disrupt chemical processes within the cell, eventually killing the bacteria or at least stopping their growth.
Plants have evolved over millions of years to protect themselves from pests, disease and extreme conditions. Those attributes are increasingly considered useful in treating the ailments that affect us in the modern world.
Tea tree oil comes from the leaves of the tea tree, which is native to southeast Queensland and the northeast coast of New South Wales, and has become a $250 million industry. It's a great natural treatment for acne and a top-selling product at natural skincare and cosmetic company The Body Shop.
Harding sees mānuka oil as being like the tea tree oil industry was 25 years ago, when it was also boutique in nature. Starting with school sores, Manuka Bioscience wants to confirm its mānuka oil formulation's effectiveness and safety in real-world trials with the aim of gaining regulatory approval for its sale around the world. Plans are in the works for a mānuka oil clinical trial for eczema, too. But the real selling point is that mānuka oil will get around the problem of antibiotic resistance.
"With antibiotics, you have one, if you are lucky maybe two or three, active ingredients," says Harding. "With essential oils, you have dozens of active ingredients that affect bacteria in different ways. It's really hard for bacteria to develop resistance to all these different compounds."
White tube test
At Wellington's Medical Research Institute of New Zealand (MRINZ), deputy director Alex Semprini has begun the hunt for the 50 children who will be needed to complete the impetigo trial. "The challenge is finding the kids presenting in the acute phase of impetigo, and we're not sure where we are going to get them," he says.
The process could take up to a year. But Semprini has been here before. As part of a previous larger clinical trial using kānuka honey to treat cold sores caused by infection with the herpes simplex virus, he helped establish MRINZ's Pharmacy Research Network, made up of community pharmacies from across New Zealand and Australia. "Pharmacists will be able to recruit children on to the trial if they're eligible," he says. "It's a good revenue stream for the pharmacies as they are facing competition from the big conglomerates such as Chemist Warehouse."
The pharmacy referrals are a relatively new decentralised approach to clinical trials designed to speed up recruitment and lower costs. The network helped Semprini recruit about 1000 cold-sore patients for the kānuka honey trial.
It found that a formulation containing just pharmaceutical-grade kānuka honey and glycerin was as effective at treating cold sores as acyclovir, the key ingredient of cold-sore antiviral drugs.
Tauranga company HoneyLab, which developed the kānuka formulation, now markets the treatment as Honevo Cold Sore. A 10g tube of the gel sells for about $25. That compares well with Zovirax, one of the bestselling cold-sore creams, which sells for the same price but comes in a 2g tube.
A handful of pharmacies in Wellington, Tauranga, Auckland, Rotorua, Napier and Gisborne will initially recruit participants for the impetigo trial.
"The pharmacist actually takes pictures of the impetigo lesions," says MRINZ study co-ordinator Gabby Shortt. "Then the child's parents or guardians take pictures of the lesions twice a day. It is an entirely paperless process."
A dermatologist then reviews and scores the photos based on a skin-infection rating that measures the puffiness of the skin and the scale of infection. Some of the children will receive a cream containing Manuka Bioscience's mānuka-oil formulation. Others will get Crystaderm, the leading antibiotic cream for impetigo.
It's a single blind trial, which means that only the researchers doing the study know what treatment each participant receives. "The creams will be served in identical white tubes," says Shortt. "But because of the smell of the oil, they might be able to tell what they have been given."
The Manuka Bioscience team is hoping for a similar result to the kānuka honey trial – evidence that the natural treatment is as good or better than leading pharmaceuticals. But strong results in petri-dish experiments don't necessarily translate into effective treatments for humans.
"We are more complex and there are more factors involved," says Semprini, who, as a practising doctor before moving into research, witnessed both the rise of antibiotics resistance and the growing demand for alternative, natural treatments.
"I've got a number of stories of patients that stopped their Western therapies for natural products and actually didn't do very well," he says.
"So I think there's a real importance to take these products seriously in terms of demonstrating efficacy and being open to the fact if they've got valid efficacy they should be considered for use.
"People are spending a lot of money on these products. They need to know that they work."
A phase III trial featuring about 300 participants will likely follow the current trial. MRINZ has a few other clinical trials for natural products in development, including an 80-patient trial for eczema using kānuka oil.
From recruiting trial participants through pharmacies to developing systems for data collection and bioinformatics, the institute is building the infrastructure to make undertaking clinical trials a realistic option for New Zealand companies. "We get lots of approaches from small companies with natural products, but few who can afford to do the clinical research," Semprini says. "What we are really reaching for is to match the pharmaceutical development pathway."
Chainsawed off the land
The small coastal town of Te Araroa at the tip of the East Cape lies a two-and-a-half-hour drive north of Gisborne and is at the heart of mānuka oil country. This is the birthplace of Sir Āpirana Ngata, the Māori statesman who represented the Eastern Māori electorate in Parliament for nearly 40 years from 1905 and whose face adorns our $50 note.
When Ngata was born in 1874, the town was known as Kawakawa, after the small tree common to the area and much of New Zealand. Māori have used kawakawa for centuries to treat everything from toothache to bladder problems, boiling the leaves and roots to make a soothing tea.
In the local schoolyard stands Te Waha-o-Rerekohu, the country's oldest pōhutukawa tree. It's estimated to be about 600 years old and when in full bloom, bristles like a beacon against the scrubby landscape. Trees need to be hardy to grow in this harsh landscape, which gets its fair share of sunshine but also wet and wild weather.
Most of Manuka Bioscience's oil is extracted from the leaves of wild mānuka trees in the area, clusters of which dot the landscape around the Karakatuwhero River, which empties into the Pacific Ocean near Te Araroa. But for decades, mānuka was bulldozed and chainsawed off the land. "The country saw mānuka as a weed; it was something standing in the way of a good farm," says Mark Kerr, a Te Araroa local and pioneer of mānuka oil production who has been extracting the oil from trees on the East Cape since 1992.
Drawn to the area more than 30 years ago by the surfing, fishing and laid-back lifestyle, Kerr began thinking about how to make a living off the land. Initially, he had another essential oil in mind.
"I really don't like to admit it, but we were looking at Australian tea tree, which was a great industry," says Kerr, who with his wife, Sue, featured in an episode of Country Calendar last year. "Then we asked the question, is there anything interesting about mānuka and kānuka?"
Kerr and a friend commissioned some research into the antimicrobial properties of mānuka and soon realised that a local Māori trust had latched on to the same idea and approached the same scientists. They decided to join forces.
The high level of antimicrobial activity detected in oil samples convinced the group that mānuka oil could take on tea tree oil – and even better it.
Later, an influential Plant & Food Research report would measure the triketone levels present in mānuka trees around the country. It found that East Cape mānuka oil contained 20-40 per cent triketone compounds. Oil from trees in other parts of the country rarely contained more than 5 per cent, except for Marlborough Sounds mānuka oil, which could muster 15 per cent triketones. Australia may produce mānuka honey in competition with New Zealand growers, but its mānuka oil has a different chemotype that doesn't imbue it with the powerful antimicrobial properties of its East Cape equivalent.
The East Cape has a potent and valuable resource on its doorstep and is now going head-to-head with tea tree oil. "We recognised early on that the benefits of the oil for human health are what would be really exciting," says Kerr, who focused on mānuka oil production through most of the 1990s, later supplementing the business with mānuka honey production and later kawakawa tea leaves.
The process of obtaining mānuka oil is dusty and laborious work. Mechanical diggers armed with trimming attachments lop about 50cm of top growth from the trees, scooping up the branches and leaves to be transferred into bins loaded on to trucks.
At a distillation plant on State Highway 35 just out of Te Araroa, Kerr dumps the bins of mānuka clippings into large steel vats. "We use the fundamental process of steam distillation, which is centuries old," he says. "Every crop requires its own fine-tuning to maximise those active ingredients."
The leaves are steamed to force water into them, collecting much of the oil in the process. The heated, oil-carrying vapour that emerges is then cooled down and separated into water and oil.
What Kerr is left with is concentrated oil and a mass of mānuka branches and leaves. Producing a tonne of mānuka oil creates about 330 tonnes of leaf waste. Kerr's team uses the bulk of the waste as compost around the mānuka trees, but another Callaghan Innovation-funded project run by Manuka Bioscience is exploring other potential uses for it, such as in wound dressings, packaging materials and bioplastics.
Bee and tree
Honeybees collect nectar from the flowering mānuka trees for honey, and oil is harvested from the leaves. It's a productive, sustainable combination that is generating income for many East Cape landowners.
But nearly 30 years on from Kerr's East Cape Mānuka Company's first foray into oil production, the industry is still very much boutique in nature, dwarfed by the highly competitive mānuka honey industry.
There are two major oil producers, the other being the New Zealand Mānuka Group based in Whakatāne. The entire industry produces just 10 tonnes of oil each year. That compares with the Australian tea tree oil industry's annual output of 800 tonnes.
But mānuka oil's bioactive ingredients see it command a huge premium. A kilogram of tea tree oil sells for $75, compared with $650 for mānuka oil. With most mānuka skin treatments containing no more than 2 per cent mānuka oil, a little can go a long way.
Early on, Kerr set up Natural Solutions, a company to sell mānuka oil, creams and soaps and later UMF mānuka honey and mānuka tea. As well as supplying the oil for Manuka Bioscience's cosmetic products, another company in Kerr's stable, Tairawhiti Pharmaceuticals, is focused on the medical applications of mānuka oil.
This area, Kerr believes, is what could really transform the mānuka oil industry and make it a much bigger part of the East Cape economy. "The existing growth in demand has given us the confidence to move into a plantation system," he says. "We have 65ha planted now. There will be another phase of growth in that plantation area to support the pharmaceutical market."
The plan is to expand the plantation, which consists of land with mixed ownership, to 110ha. Owners receive a royalty from the oil production. The trees take about five years to reach maturity, so in the coming years, oil will increasingly be harvested from plantations rather than wild trees.
Between the oil production, beekeeping operation – which tends to about 800 beehives – and a cafe and visitor centre, Kerr employs 17 staff, increasing to about 30 during summer and autumn for the harvest. He plans to add up to 20 more staff in the next five years. Not bad for an area with a population of about 600. "Growth in pharmaceuticals could potentially result in a few hundred people being employed," says Kerr. "The work over recent years has shown that there's something unique here on the Cape." It will hinge on the success of clinical trials, such as the impetigo study currently under way, showing that mānuka oil-based therapeutics are at least as good as existing antibiotics.
However, experience has taught Kerr to be patient. "It takes time with any new essential oil on the market for people to be comfortable using it. That's why building a body of research to support it is so important."
Harding has ambitions, based on advice from her regulatory adviser, to have an over-the-counter skin-cream treatment for impetigo within three years. "We've got a lot of in vitro data from the lab and that carries a lot of weight as we've done comparisons with tea tree oil and mānuka honey in antiseptics and antibiotics.
"If we can be involved in the fight against antimicrobial resistance, that's huge for us."