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Discovery Down Under

From century-old medicines to genetically engineered livestock, biological and medical research are thriving in New Zealand.

Linda Nye

New Zealand has several unique qualities that make it an ideal breeding ground for research and innovation. Our economy is based on agriculture, and the quest for improved profitability in the farming sector leads to agricultural discoveries that have application in human health. We are geographically removed from the rest of the world; this distance not only protects us from the spread of diseases such as foot and mouth disease and bovine spongiform encephalopathy (“mad cow disease”), but allows us to research innovative ideas, unhindered by established conventions. We have a tradition of ingenuity and innovation, known locally as the number 8 wire tradition, referring to the many uses that 8-gauge fencing wire is put to in the farming community. Our native flora and fauna constitute a large untapped biochemical resource that is only now being recognized and researched, and has already resulted in some exciting advances.

New Zealand is an island nation with only 3.8 million residents, making it one of the developed world’s poor relatives when it comes to research and development. This situation is rapidly changing, however, with R&D expenditure increasing by 6.2% per year. R&D spending was NZ $1107 million (~US $500 million) in a 1997–1998 biannual report (1). An estimated 70% of the research in New Zealand is carried out by the government and university sectors; 53% is government-funded. Health research accounts for ~11% of all R&D in New Zealand.

Research is alive and well. A number of breakthroughs have been made, and many novel compounds have been identified and selected for further research. Most of the biomedical research in New Zealand is in a preclinical phase, and overseas collaborations provide the necessary funding for clinical trials.

Traditional Maori medicine and native plants
Researchers are turning their attention to the native plants that New Zealand’s indigenous people, the Maori, have traditionally used in medicines. Industrial Research Ltd. (IRL), in Lower Hutt, is one company working in collaboration with local Maori groups to identify bioactive compounds that may lead to the development of new products.

Of particular interest is an agreement between some Maori groups, the Sisters of Compassion, and IRL in June 2000. This agreement allows IRL researchers to investigate samples of preserved antique health remedies in order to identify the plants used to manufacture them. In the 1890s, Roman Catholic nun Suzanne Aubert commercialized nine remedies using New Zealand native plants and Maori knowledge. Unopened bottles still exist for four of nine remedies in the archives of the Sisters of Compassion.

The flavonoids in these remedies are being analyzed and compared with extracts from native plants. In a collaborative effort with the Victoria University in Wellington, DNA from the remedies is also being matched with plant DNA to assist in identification. Results of analyses are likely to become available in early 2002.

Native plants have yielded several interesting compounds that may lead to therapeutic products. The Totara, a giant native tree (Podocarpus spp.), yields a potent natural diterpenoid antibiotic, totarol.

Totarol is an effective antibacterial agent, with activity in vitro against several gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) (2), but it has been shown to be ineffective in vivo (3). IRL has been investigating the minimum structural requirements needed to retain the antibacterial activity of totarol, but also to be effective in vivo. A series of analogues showed that the phenolic group is essential for antibacterial activity (4), and work with these compounds is continuing.

The manuka tree (Leptospermum scoparium) has been used in traditional Maori medicine for centuries. The oil extracted from the leaves and terminal branches is an antibacterial, antifungal, and anti-inflammatory agent. Antibacterial activity varies, depending on where the trees from which the manuka oil is extracted grow. Manuka trees from the East Cape of New Zealand produce an oil that contains the highest level of β-triketones (leptospermone, flavesone, and isoleptospermone) and the highest level of antibacterial activity (5).

Manuka honey
Honey produced by bees that feed on manuka flowers also has unique properties that aid in wound healing (6). In 1995 a special unit was set up at the University of Waikato, Hamilton, specifically to investigate potential therapeutic activity and uses for this natural product.

Honey has a number of properties that make it useful in treating wounds: It has a potent antibacterial action and has been shown to be effective in clearing existing infection in wounds and preventing infection. It also has anti-inflammatory properties and aids in the healing of wounds (7, 8). Researchers believe that the antibacterial action is due to the presence of hydrogen peroxide, produced by a glucose oxidase enzyme that is secreted from the hypopharyngeal gland of the bee and used in the formation of honey (7). The hydrogen peroxide is produced continuously by this enzyme and at a level that does not damage human tissue. Some honeys have additional plant-derived antibacterial effects, and manuka honey has a very high level of plant-derived anti-bacterial effect (7).

The active ingredients in Manuka honey (which have yet to be identified) give rise to its unique antibiotic properties. These potent ingredients are only known to exist in honey produced from Leptospermum spp. plants and have been labeled the “unique manuka factor” (UMF) (9). P. C. Molan has determined the potency of manuka honey by comparing it in an agar diffusion assay with phenol. Manuka honey with a UMF of 10 has the same antibacterial potency as a 10% phenol solution.

Manuka honey is effective against epidemic strains of MRSA and vancomycin-resistant Enterococcus (VRE). Results of laboratory tests have shown manuka honey to be nearly twice as effective as other types of honey (9, 10). Although no clinical trials have been done on manuka honey, experience in New Zealand has shown the beneficial effects of manuka honey on wound healing; and clinical papers are beginning to surface that show the efficacy of manuka honey when used on patients for whom antibiotics have previously failed (10, 11).

Pharmaceuticals in clinical trials
Several New Zealand–based discoveries have progressed to the clinical trial phase. Genesis Research and Development Corp. (Auckland) is the largest and by far the most prolific of New Zealand biotech companies. The company has two products currently in clinical trials: Pvac for the treatment of moderate to severe psoriasis, and Avac for the treatment of asthma.

Pvac is a Mycobacterium vaccae derivative. It is administered by intradermal injection over a 3-week period and has produced good responses in patients with moderate-to-severe psoriasis. The results of an initial Phase I study in the Philippines were extremely encouraging, with patients showing clinically significant responses and good tolerance (12). A Phase II trial just completed in the United States has confirmed that Pvac is effective in patients with moderate-to-severe psoriasis who have not had previous treatment with immunosuppressant therapies such as methotrexate, cyclo sporin, or UV light treatment.

Avac, a second Mycobacterium vaccae derivative, is in a Phase I clinical trial in New Zealand involving 40 patients. Avac is administered intranasally and is being tested for efficacy in allergic asthma. Further investigations into Avac’s effectiveness in atopic dermatitis and atherosclerosis are under way.

Virionyx, another Auckland-based company, received clearance from the U.S. Food and Drug Administration in March 2001 to begin a Phase I clinical trial with 20 patients for its anti-HIV drug PEHRG214, a passive immunotherapeutic pharmaceutical. This drug contains purified polyclonal IgG antibodies to critical epitopes on HIV, which are not produced by the human immune system. It is designed to be used in patients who are HIV positive. It has been shown to be capable of destroying HIV in recent laboratory experiments, and the Phase I trials at the Beth Israel Deaconess Center in Boston will give more information about the toxicity and pharmacokinetic profile of this novel therapeutic.

University research
New Zealand’s universities conduct significant numbers of preclinical investigations, and most of the R&D in New Zealand takes place within the universities. The Auckland Cancer Society Research Centre (ACSRC), a division of the University of Auckland, has several research projects under way to identify potential leads for therapeutic products that will be effective in cancers that were previously difficult to treat and have reduced side effects.

Studies conducted at ACSRC have led to clinical investigations for several novel anticancer drugs:

• Dimethylxanthenoneacetic acid (DMXAA) is a synthetic, low-molecular weight compound that has shown in Phase I clinical trials in the United Kingdom to be a selective inhibitor of tumor blood flow (13). It is currently in clinical trials in New Zealand and the United Kingdom.
• Amsalog (CI-921), a topoisomerase II inhibitor, has been the subject of a Phase I clinical trial just completed in the United Kingdom. This trial was to evaluate its toxicity and pharmacokinetic profile and to establish a dosing schedule for further studies (14).
• N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA, XR5000) is a mixed topoisomerase I and II poison that was developed at ACSRC. It has been taken through to Phase II trials by Xenova plc (Berkshire, England). Preliminary results of the Phase II efficacy trials in Europe were announced by Xenova in February 2001. The company announced that although there had been a number of minor responses noted, it would not pursue development of DACA. Instead, it would focus on further development of its two second-generation dual topoisomerase inhibitor compounds, one of which was also developed at ACSRC (XR5944). Studies conducted in collaboration between ACSRC and Xenova have shown XR5944 to be a highly active and well-tolerated anticancer agent (15).
• CI-1033 is a novel drug candidate that ACSRC also developed in collaboration with Pfizer Global Research. This compound is an irreversible inhibitor of the Epidermal Growth Factor Receptor (EGFR) and is currently in Phase I clinical studies across the United States (16). Researchers believe that CI-1033 may be potentially useful either as a single agent or in combination therapy for solid tumors of the breast and ovary (17). Following the success of CI-1033, ACSRC is now looking at drugs that will interrupt other growth-signalling pathways of cancer cells.

ACSRC is also researching the synthesis of prodrugs, novel nontoxic chemicals that require hypoxic conditions and ionizing radiation to transform them into active and potent anticancer agents. These prodrugs will provide new clinical options for previously difficult-to-treat hypoxic tumor cells that do not respond well to traditional radiotherapy. The current research is expected to lead to preclinical candidates within 3 years.

Nutraceuticals
R&D in the nutraceutical arena is on the increase in New Zealand. Several companies are investigating products that are dietary components, and as such, are gaining favor with the public.

Products from the New Zealand dairy industry make up 25% of the country’s exports. In the mid-1980s, the University of Auckland undertook research to investigate any link between milk consumption and Type I diabetes. Researchers found that there was strong correlation between the incidence of Type I diabetes and the consumption of milk containing β-casein A1 (18). A correlation between the consumption of β-casein A1 and ischemic heart disease has also been suggested (19). A2 Corporation (Dunedin) and the University of Otago Medical School, Dunedin, are investigating this link.

A2 Corp. was formed in February 2000 and has developed a DNA-based screening test to identify cattle homozygous for β-casein A1. Specific breeding programs have been developed to separate herds that will produce milk that is free of this casein. β-Casein A1 differs from the A2 variety by a single amino acid substitution in position 67 of the molecule: β-Casein A1 has histidine, whereas A2 has proline.

The production of specific β-caseins in milk is genetically determined by a codominant gene. Researchers an ticipate that by identifying cattle that are homozygous for β-casein A1, and by separating herds and selectively breeding β-casein A2– producing cows with A2 homozygous bulls, pure β-casein A2 milk will be produced, and the risks of Type I diabetes and coronary heart disease will be reduced in susceptible people.

Blis Technologies Ltd. (Dunedin), started last year by Otago Trust Ltd. and a group of investors, is another company launching into the nutraceuticals market. It filed in ternational patents following the discovery of a naturally occurring anti bacterial protein called salivaricin B, which is produced by Streptococcus salivarius, and appears to confer immunity against streptococcal sore throats (20). Blis Technologies anticipates having a product available in tablet form in the near future.

Genomics
In April, AgResearch, a government-owned R&D company, announced the successful location of the Booroola gene, which greatly increases fecundity, on the sheep genome. It is a codominant gene found on the human chromosome 4 and the sheep chromosome 6; and it has an additive effect on fertility that increases the number of eggs released each cycle. Sheep with one copy of the gene are more likely to have twins or triplets, and those with two copies of the gene can produce up to five offspring per gestation.

The mapping of the Booroola gene at AgResearch will lead to the discovery of the gene’s precise role in regulating fertility and has implications for treating human infertility and for developing contraceptives.

Untapped resources
When I spoke to scientists around New Zealand, it was clear that our country has abundant natural and scientific resources. Although research is underfunded, these resources are being put to good use; most organizations in the New Zealand research arena are working together for the good of all. A surprisingly small amount of duplicate work occurs; cooperation between researchers allows the relatively small amount of funding to be spread around and permits researchers to specialize in their given fields.

Much of the native flora and fauna are yet to be identified, so New Zealand is sitting on a potential biochemical gold mine. Because of our time zone, we were the first country to usher in the new millennium—we don’t know just where it will lead us, but we are sure it will be interesting.

References

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6. Betts, J.; Molan, P. C. A pilot trial of honey as a wound dressing shows the importance of the way honey is applied to wounds. Presented at European Wound Management Association Conference, Dublin, Ireland, May 2001.
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20. LANTIBIOTIC Patent application WO0127143, published April 19, 2001.

Pauline Hamilton is a pharmacist and freelance writer based in Oamaru, New Zealand (hamlin@es.co.nz).