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New study sheds light on effectiveness of cholesterol medication in individuals

A study by a team of Victoria University of Wellington scientists spotlights the role of gene networks in how people respond to one of the world’s most prescribed medications.

4 October 2019
two men with building in background

The research team investigated the genetic network response to cholesterol-lowering drugs called statins, a medication prescribed to about 30 million people worldwide. The researchers say it is a significant step towards more targeted, personalised medication.

The work was begun by Dr Bede Busby as a PhD student at the University, working with chemical geneticists Professor Paul Atkinson and Dr Andrew Munkacsi (pictured) from the University’s School of Biological Sciences and Centre for Biodiscovery. It appears in the prestigious scientific journal npj Systems Biology and Applications, published by Nature Research.

“Statins work and deservedly have a good reputation. But 15 percent of patients suffer painful side effects and 50 percent have inadequate response,” says Professor Atkinson. “So what we’ve found out about how statins work can lead to modifying statins to make them more precise, based on personal differences in genetic interaction networks. The aim is to make them effective for people they don’t currently work for (these people are resistant to statins) and this requires understanding complex traits, that is traits that involve many genes, as is the case with all drug responses.”

“To explain a complex trait, it was previously thought that all you had to do was add up the contributing genes—tallness, for example, would be the sum of more than 200 genes,” he says. “But what we’ve shown is that the synergistic interactions between each of the genes turn out to be just as important. The synergies form gene networks and these differ in individuals, so you have to look at the gene network variation of individuals to get a complete picture of how traits are specified by genes and inherited.”

The study of complex traits needs simplifying short cuts so the researchers used baker’s yeast, which is a widely used and a very productive model to study human genetics and how therapeutic drugs work.

“We can do things with yeast that you can’t yet easily do with human cells,” explains Dr Munkacsi. “If you want to know how 6000 genes work synergistically together, you study all pairwise combinations of genes—this is classic methodology in yeast genetics that we adapted to study different genetic backgrounds and it is not yet adapted to study the 21,000 human genes.”

Dr Munkacsi says the research specifically used yeast strains that were resistant to statins. “We did experiments in the resistant yeast strains and worked out the biology of those interactions—that means we have a sense of what processes are involved in that resistance.”

“We integrated advanced biology experimentation, mathematics, statistics, network medicine and adapted social network analysis for complex genetic data in a new approach to looking at drug response. We’re continuing to use this methodology to study other drugs and diseases,” Professor Atkinson says.

“We’ve opened a box that hasn’t really been considered before—it’s experimentally difficult to systematically consider both genetic backgrounds and genetic synergistic interactions so pharmaceutical companies haven’t done it in their drug discovery process,” explains Dr Munkacsi. “But we’ve shown that yes, you should consider both of these as part of drug discovery—used early in the process it could save companies millions of dollars if it identifies undesirable responses.”

All nine co-authors of the paper are currently or formerly based at the University, with Dr Busby now at the European Molecular Biology Laboratory in Heidelberg. “Typically publishing papers requires an international effort, but this one is all New Zealand—and impressively the majority are postgraduate students in our Chemical Genetics Laboratory at Victoria University of Wellington,” says Dr Munkacsi.

“It’s very satisfying to get this research out there, and like all significant research it’s not the end of the road—it opens doors,” says Professor Atkinson. “Our work demonstrates principles that were not necessarily understood before, that also can be applied more widely—to other drugs and diseases, for example. We haven’t discovered a magic bullet but we have discovered some good science.”


Solving a hidden threat to New Zealand’s meat and dairy industry

Beef and lamb exports are one of New Zealand’s major industries, potentially exceeding $3 billion for the first time this year. But a high prevalence of veterinary pathogens causes high rates of animal death, suffering, and decreased production, and diseases like pneumonia in sheep and mastitis in cows lack effective vaccines.

Associate Professors Bridget Stocker and Mattie Timmer from Victoria University of Wellington are working with AgResearch to help address this problem, developing vaccines to help prevent ovine pneumonia, with promising early results.

This is the next step in an ongoing project for the University researchers, who have spent the past few years developing a new class of vaccine adjuvant—which is an additive to a vaccine that improves the host’s immune response and increases vaccine efficacy. During the development of this adjuvant class, the researchers, along with their PhD student Amy Foster, worked with Professor Sho Yamasaki from Japan, one of the world’s foremost experts in immunology.

“To have an effective vaccine, you need the right adjuvant for the right pathogen,” Associate Professor Stocker says. “There is a gap in the market for adjuvants that elicit a strong cellular immune response in addition to an antibody-mediated response. This is a need we are addressing.”

The adjuvant created at Victoria University of Wellington activates a specific immune pathway. This pathway is related to a number of human diseases, such as meningitis and tuberculosis, but it is also related to the pathogens that cause ovine pneumonia.

With the help of Viclink, the University’s commercialisation arm, and funding from the Ministry of Business, Innovation, and Employment, Associate Professors Stocker and Timmer connected with Drs Neil Wedlock, Natalie Parlane and Axel Heiser from AgResearch, experts in animal vaccines.

“We hadn’t initially considered our adjuvant in relation to animal vaccines, but Viclink suggested this as a possible commercialisation pathway,” Associate Professor Stocker says. “So far our early trials show a lot of promise, and we’re very excited about the next steps.”

“We spend a long time undertaking basic research to understand how particular classes of molecules interact with the immune system. It’s great to be able to take this knowledge from an academic setting to one that could help solve a major issue in the New Zealand farming industry.”

So far, the research team have worked to refine their adjuvant in the laboratory and develop a vaccine for use in sheep. They have completed the first phase of testing and will enter the second phase over the coming months.

“In the first proof-of-concept trial the adjuvant performed as good as, if not better than, currently available adjuvants,” Associate Professor Timmer says. “It is still early days, but it bodes well for future testing.

“Science is never straightforward—if it were there would be no problems left to solve—but we are quietly optimistic, and early indicators suggest we are heading in the right direction.”

Jeremy Jones, Senior Commercialisation Manager at Viclink, says he is very excited to be working with the team to progress their technology towards market.

“Each set of results we get makes us more excited about this project,” Jeremy says. “The team they have assembled makes our job much easier, as we have all of the expertise we need to generate a very strong data package, and the involvement of the team at AgResearch has accelerated this project, allowing us to gather data in a large animal to bolster the laboratory work done here at the University.

“On a recent trip to the US to engage with the animal health market it was clear that there is an imperative from these companies to find technologies that enabled the reduction or elimination of antibiotics from the food-chain. An effective vaccination program and use of immunostimulants such as these developed by Associate Professors Stocker and Timmer and their team are the best line of defence for the industry."


Researchers make potential breakthrough in cancer drug development

A Victoria University of Wellington research team has developed an exciting new lead in the search for cancer treatments, creating alternative versions in the laboratory of a rare natural compound that targets some types of cancer.

The research team, led by Dr Joanne Harvey from the School of Chemical and Physical Sciences, successfully created several synthetic alternatives to the compound, TAN-2483B, which is found in some fungi. Previous research has shown that this compound may be effective against the development of some types of cancer and can also help with bone degenerative diseases like osteoporosis, but researchers haven’t been able to find or create it in big enough quantities for it to be useful in drug development, Dr Harvey says.

“TAN-2483B has previously only been isolated in small quantities or as mixtures, so it’s very exciting that we’ve been able to create synthetic alternatives in larger quantities in the lab,” Dr Harvey says.

Now they’ve created the alternative compounds Dr Harvey and her team plan to recreate the natural compound in the laboratory as well, which will mean that the therapeutic potential of TAN-2483B can be fully explored.

“Our alternatives and the original compound target different cancer enzymes, so if we can create all of them in good quantities in the lab we will have even more avenues for cancer drug development,” Dr Harvey says.

As well as creating larger quantities in the laboratory, Dr Harvey and her team have been working to make the production process affordable and more accessible. They used a cheap and readily available sugar as the main building block of the alternatives they have developed and are investigating how to make the rest of the production process more efficient as well, Dr Harvey says.

“If we can cheaply and easily produce large quantities of these compounds, it will enable us to perform the thorough tests needed to take them to the next stages of cancer drug development,” Dr Harvey says.

This work was published in Chemistry—An Asian Journal.


Mātauranga Māori could stop kauri dieback in its tracks

Research led by Victoria University of Wellington’s Dr Monica Gerth in collaboration with iwi has discovered molecules from New Zealand native plants could hold the solution to kauri dieback.

“Our research has discovered that some compounds found in kānuka cause an immediate loss of motility, or movement, of the infectious spores of the microbe that causes kauri dieback disease,” says Dr Monica Gerth from the University’s Centre for Biodiscovery and School of Biological Sciences. “If the spores can’t swim, they can’t make it to a kauri root to infect. These compounds could stop this pathogen from moving through soil and infecting kauri trees.”

These results came from a new collaboration between scientists and kaitiaki from iwi, Dr Gerth says, after colleague Chris Pairama (Te Taou, Ngati Whaatua, Waimauku) connected the research team with Ian Mitchell (Te Uri Taniwha, Ngāpuhi, Waima).

“Being from the north where kauri is common, Ngāpuhi have extensive knowledge about kauri and how plants interact with the forest, and we hoped that we could combine their mātauranga Māori and our scientific knowledge to address the serious problem of kauri dieback disease.”

She says Ngāpuhi knowledge and experience shows that a healthy forest involves three stages of plants— ‘first wave’ plants that cleanse and prepare the soil, ‘second wave’ plants that encourage fertility and growth, and ‘third wave’ plants, including kauri, that bring permanence and stability.

The research group studied four ‘first wave’ plants—kānuka, karamū, kawakawa, and nīkau—to see if the cleansing activity of these plants was due to anti-microbial properties, Dr Gerth says. In the end, testing showed that kānuka extract was most effective at stopping the pathogen.

Mātauranga Māori and scientific knowledge were combined at every stage of this project and collecting and testing the plants was a collaborative effort, Dr Gerth says.

“This project was about mutual trust and collaboration, and it was very important to us to create an ethical collaboration,” Dr Gerth says. “These plants are taonga to Māori, and therefore the right of mana whenua to practice kaitiakitanga (stewardship) should be acknowledged and respected.”

Dr Gerth and her colleagues hope to continue their search for new compounds, while also exploring how their findings can be applied to protect kauri trees in the field.

“Kauri dieback is one of the biggest crises ever to face New Zealand's forests. If we lose kauri, we lose not only a unique ecosystem, but also a key part of part of New Zealand’s identity, history and culture,” Dr Gerth says.

Kia mate te ngarara o te kauri, kia whakaora te mauri o te ngahere. Kauri ora, mauri ora!

This research was funded by the Ministry of Business, Innovation, and Employment, and published in the Journal of the Royal Society of New Zealand. The manuscript is freely available online at: http://dx.doi.org/10.1080/03036758.2019.1648303.

In addition to Dr Gerth, Mr Mitchell and Mr Pairama, the cross-disciplinary research team included Dr Scott Lawrence from the University of Otago, Professor Nigel Perry and Ms Elaine Burgess from Plant & Food Research, Associate Professor Wayne Patrick from Victoria University of Wellington, and Dr Amanda Black from Lincoln University.


Germs and geothermals—a uniquely New Zealand collaboration

Dr Rob Keyzers from the School of Chemical and Physical Sciences is leading a long-running, uniquely New Zealand research project to help find new sources of antibiotics.

The collaboration is looking at a group of organisms called ‘extremophiles’—organisms that live in extremely hot or extremely cold environments unsuited to human habitation. For the past several years, the research—involving scientists from Victoria University of Wellington, GNS Science, the University of Auckland and the University of Canterbury—has focused on one organism that lives around geothermal vents in New Zealand.

And although the project has encountered many hurdles and setbacks, Dr Keyzers says they can successfully point to research spanning organism discovery through to synthesis.

“This project was all about the right people coming together in the right environment with the right resources, all of which were found in New Zealand,” Dr Keyzers says.

“It started in 2011 when I was looking for new sources of antibiotics in the natural world,” Dr Keyzers says. “Nature has been a wonderful source of antibiotics so far, but we always need new drugs that kill pathogens in new ways. Extremophiles were an ecological niche that hadn’t been explored much, so I thought it might be a good place to start looking.”

Dr Keyzers contacted Matthew Stott, formerly at GNS Science and now the University of Canterbury, who is an expert in growing bacterial extremophiles from geothermal environments.

They started looking at one particular extremophile for natural products that might lead to a new antibiotic. Dr Stott had recently sequenced the genome of that organism, which meant they could examine the DNA for sequences already known to be helpful in creating antibiotics.

“Matt’s organism had the potential to make four useful molecules written into its genetic code,” Dr Keyzers says. “We had my Master’s student, Emma Aitken, test the organism to see if any of these molecules were actually being produced, so we could test it for potential applications. She found one—a peptide that is part of a known class of antibiotics, which was very exciting.”

The next step was gathering enough of this molecule to test it for potential applications. This turned out to be more of a challenge than Dr Keyzers and his team were expecting—the organism would only grow under very specific conditions, and only produced a very small amount of the compound.

“Emma went through 1200 petri dishes to grow this organism,” Dr Keyzers says. “It would only make the molecule we wanted if we grew it in a petri dish on a certain type of agar. Even after that, we could only gather around 400 micrograms (0.4 g) of the molecule.”

Dr Keyzers began looking at options to synthesize the molecule and contacted Distinguished Professor Dame Margaret Brimble from the University of Auckland, a world-leading expert in synthetic chemistry. Coincidentally, Dame Margaret had also recently developed an interest in extremophiles.

“Dame Margaret and her team were able to synthesize the molecule using some very interesting chemistry techniques they had developed,” Dr Keyzers says. “They were only able to make a small amount, but it was enough to start testing the molecule.”

Unfortunately, the tests were not promising—the molecule didn’t seem to have any effect on the bacteria they tested it on. However, Dr Keyzers and his colleagues were only able to test the molecule against a small group of bacteria.

“The molecule could be a successful treatment for other bacteria we couldn’t test against, or it could be an anti-fungal,” Dr Keyzers says. “We would need to do further tests to find this out.”

Although the tests themselves were unsuccessful, Dr Keyzers says this research project has been hugely beneficial in other ways.

“We were able to get our work published in a well-regarded journal, Chemical Science, and put New Zealand on the map as a leader in this area of chemistry,” Dr Keyzers says. “There have been very few other cases where a research collaboration has been able to run the whole gambit from discovery to synthesis.

The research group also followed a vigorous identification method, which Dr Keyzers hopes will set a high standard in this field, and Dame Margaret and her team at the University of Auckland were able to develop several improvements to the synthesis process as well, Dr Keyzers says. They were also able to exploit an ecological niche—geothermal extremophiles—that is very New Zealand-centric and is an area where New Zealand can offer unique research possibilities in both geothermal and extremophile niches.

“It needed someone who knew about extremophiles and someone with knowledge of my area of chemistry, both of which are reasonably rare, as well as a microbiologist to provide material for me to test that I could then pass on to an expert in synthesis to create. We looked at a fairly unusual area with extremophiles and were able to achieve all these great things here in New Zealand.”

“Collaborations like this are one of the benefits of living in New Zealand,” Dr Keyzers says. “We have a small community of researchers here, brought together through the Maurice Wilkins Centre of Research Excellence, who all know each other and can easily work together, using New Zealand’s natural resources to push forward projects like ours.”

Dr Keyzers plans to continue his work on this project and hopes to bring in the expertise of School of Biological Sciences colleague, Dr Jeremy Owen. Dr Owen is a specialist in taking genetic codes that produce certain molecules from one organism and transplanting them into another organism to help them grow faster.

“Jeremy’s expertise can help us produce molecules faster, as well as take DNA from anywhere and grow it,” Dr Keyzers says. “Along with Margaret’s expertise in synthesis, we can now discover and grow potentially helpful molecules much faster, which is a very exciting prospect.”

The researchers acknowledge all governance entities representing owners and shareholders (tangata whenua) of Māori Freehold Lands of Aotearoa New Zealand, in this case Tikitere Trust, who have kindly consented to research and discovery being conducted on their land.


Antifungal activity of Feijoa brings Research Article of the Year Award to Centre for Biodiscovery PI

Many of us have heard of antibiotic-resistant bacteria, either through the media or perhaps knowing someone who died from such a bacterial infection. Just as there are bacterial infections resistant to antibiotics, there are fungal infections resistant to antifungal drugs.

Fungi are microbial organisms (not visible to the naked eye) that can infect plants, animals and humans. Yes, mushrooms are fungi, but not all fungi are mushrooms. Approximately 300 fungal species are known to be pathogenic to humans; these include well-known species such as Candida albicans (the causal agent of vaginal yeast infection and oral thrush) as well as the numerous species that cause athlete’s foot.

Unfortunately, not all fungal infections are able to be treated successfully. Fungal infections cause approximately 1 million deaths per year, an alarming number that exceeds the annual deaths caused by breast cancer as well as those caused by malaria. And though people are not currently dying from vaginal yeast infections, oral thrush or athlete’s foot, there is potential for these fungal species to evolve resistance to antifungal drugs.

A recent article published in The New York Times (6 April 2019) profiled Candida auris, a fungus (specifically a yeast) resistant to antifungal drugsspreading around the world killing a significant number of people since 2009. Prolonged exposure to high doses of antifungals (as in people with compromised immune systems such as the ageing senior population, cancer patients receiving radiation or chemotherapy treatment, and organ transplant patients), is a means for C. auris, and other fungi, to evolve resistance.

The current clinically-approved antifungal drugs are divided into four classes based on their mechanisms, or ways they work. This means a fungus has to overcome merely four mechanisms in order to become resistant to currently-available drug treatment. One potential solution to treating C. auris is combination therapy where lower doses of more than one drug will be used to treat an infection. However, this solution is limited as some drugs cannot be combined.

Developing new antifungals

For these reasons, it would be ideal to identify and develop a new antifungal drug that works by a new mechanism distinct from the current four classes of today’s drugs; this would add another hurdle in the path to resistance. Developing a drug that will target the fungus only and not affect the biology of uninfected cells in the body is not easy and is the reason why there is a shortage of antifungal drugs.

Nature is a proven source to discover the next generation of antifungal drugs as most existing antifungal drugs have been based on natural compounds. As C. auris has not yet been reported in New Zealand, our plants and soil may contain the key to an antifungal drug effective at combatting C. auris.

Research in my lab at Victoria University of Wellington, in collaboration with Drs Rob Keyzers and Michael Jackson as well as the feijoa breeder Nigel Ritson at Foretaste Feijoa Fruit Ltd (Takaka), has identified compounds in the peels of feijoa that inhibit the growth of Candida species that are closely related to C. auris; this work was recently published in The Journal of Agricultural and Food Chemistry. These compounds work by targeting fungal-specific molecules that are not targeted by the four classes of today’s antifungal drugs – thus it will be good to test these compounds against C. auris and other antifungal-resistant species.

Written by Dr Andrew Munkacsi

His recently published article has also won the Journal of Agricultural and Food Chemistry 2019 Article of the Year Award.


University grant recipients include vaccine to treat drug addiction

Victoria University of Wellington scientists developing ground-breaking new vaccines to treat drug addiction have received one of fifteen $150,000 Explorer Grants from the Health Research Council of New Zealand.

Victoria University of Wellington-led research received three of the Explorer Grants for 2019, which were announced this morning.

Addiction to drugs of abuse such as nicotine, methamphetamine, cocaine and heroin could all be treated more efficiently and successfully as a result of the project led by Dr Benjamin Compton (pictured) from the University’s Ferrier Research Institute and including Dr Lisa Connor from the School of Biological Sciences.

The treatment they are developing incorporates an approach known as immunopharmacotherapy.

Addictive drugs are small molecules that easily cross people’s blood brain barrier and bind themselves to receptors, triggering reward signals. Using immunopharmacotherapy, a vaccine induces drug-specific antibodies that bind themselves to the drug, preventing it from crossing the blood brain barrier and acting on the central nervous system, thereby reducing its addictive effects.

“Despite advancements and many promising pre-clinical findings, decades of research investigating immunopharmacotherapy as a treatment option for drug addiction has not yet resulted in a vaccine candidate demonstrating efficacy in final clinical trials,” says Dr Compton.

“This funding from the Health Research Council will enable us to develop and assess an exciting new synthetic vaccine platform that could pave the way for the first efficacious immunopharmacotherapy for humans, profoundly changing the way physicians can medicate for drug addiction.”

It is envisaged the vaccine platform could be easily adapted to help treat multiple drug addiction disorders.

“Our research has the capacity to provide better outcomes for patients—including avoiding the side-effects associated with current anti-addiction medications—as well as reducing the burden harmful drugs have on society, which is estimated to cost the New Zealand economy $1.8 billion a year,” says Dr Compton.

In a second Health Research Council-funded project, Dr Wanting Jiao, also from the Ferrier Research Institute, is using the computational power of quantum and molecular mechanics to investigate a previously hard-to-access tuberculosis (TB) enzyme and design an antibiotic to fight it.

“We will make possible the development of a new generation of anti-TB drugs in a considerably shorter period of time and at greatly reduced cost than current methods allow,” says Dr Jiao, who is collaborating with scientists from the University of Otago.

The technique could also be used in the battle against other pathogenic bacteria, an international health priority due to the global rise of multidrug-resistant bacteria.

“Our novel computational methods will vastly improve the ability to design new classes of highly potent and selective enzyme-inhibiting antibiotics,” says Dr Jiao. “They will overcome the problems that plague existing techniques and promise to revolutionise drug design.”

The third Victoria University of Wellington project is led by Professor David Ackerley from the School of Biological Sciences and includes collaborators from the Malaghan Institute of Medical Research, based at the University, Johns Hopkins University in the United States, and the University of Auckland. The team aims to advance cellular regeneration research and degenerative disease modelling.

Dr Compton, Dr Jiao and Professor Ackerley are all active members of Victoria University of Wellington’s Centre for Biodiscovery.

The University’s Vice-Provost (Research), Professor Margaret Hyland, says they highlight the University’s commitment to improving health and wellbeing.

“The Ferrier Research Institute has a long and proud history of drug discovery and that continues with the two projects funded today. Other important health research is being conducted elsewhere in the University too, not least in other parts of the Faculty of Science, home to another of today’s supported projects, and in the Faculty of Health we established in 2017,” says Professor Hyland.

She adds that the three projects illustrate how Victoria University of Wellington researchers “collaborate across disciplines, institutions and indeed countries to incorporate wide perspectives in their endeavours and ensure the highest-quality results”.