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“We’ve encountered a lot of complexity along the way. Humans are unique and every sample is variable and affected by factors like age, so we’ve put a lot of work into getting these models consistent.” Research FellowDr Caitlin Oyagawa and Senior ResearchTechnicianWoo Lee in the Hugh Green Biobank will lead the testing that will help the team understand if, and how, the molecules they discover block inflammation and cross the blood-brain barrier. Dragunowhas beenworkingwith neurosurgeons since the 1990s to build the scientifically-valuable tissue collection. He says one of the Biobank’s key strengths is that it reflects New Zealand’s unique and diverse population. This ensures that local patients, reflecting Aotearoa’s rich heritage, are represented in the data, addressing potential differences in drug response not captured in predominantly European clinical trials. “This was one of the two main reasons for establishing the Hugh Green Biobank,” says Dragunow. “The other is that, unfortunately, traditional approaches of testing drugs using animal models, or human brain cells that have been immortalised for research, have largely failed to deliver effective medications for brain diseases in people. “We’ve spent about 15 years developing methods to generate advanced patient-derived brain cell models for drug testing that more closely reflect disease in people. “We’ve also pioneered a screening method which accurately measures drug effects on those brain cells. “Our approach is unique on a worldwide scale and driven by the generous brain tissue donors and their families as well as the wonderful neurosurgical teams at Auckland Hospital. “We are now in a position, with this new funding, to really make an impact and hopefully honour the wishes of the brain tissue donors by developing effective medications for brain disorders,” Dragunow says. Finding the one-in-a-billion Leading the high-performance computing element of the project is Dr Jack Copping, a computational chemist trained by Flanagan who specialises in large-scale molecular screening. His work involves screening vast ‘compound libraries’, which can contain billions of molecules. “There are libraries out there with tens of billions of molecules. While fantastically large, they represent only a small fraction of molecules that could be relevant for treating disease,” Copping says. “We’re dealing with enormous datasets, and even a tiny error in a file can cause the whole system to fail, so a lot of our work at the moment is about making sure everything is clean and usable.” Copping adds that NeSI is giving the research a globally unique leg-up. “We are fortunate that New Zealand has a national supercomputing system,” he says. “There are many places in the world that do not have that capability.” As the scale of the search grows, so too does the need for smarter tools. Rather than simulating every molecule against the drug binding site on a protein, researchers are training neural networks (a type of AI model) to recognise patterns, learning which types of molecules are most likely to pass the digital screen. “The idea is that we can use machine learning to predict which molecules are worth testing,” says Copping. “That allows us to expand the search upward from one billion and hopefully reduce the search time from months to days.” The final stage – reaching patients With clinicians already involved, including neurologists Dr Zoe Dyer and Dr Nicholas Child, and neurosurgeons including Mr Jason Correia andMr Patrick Schweder, the pathway to patients is built in from the start. This ensures researchers consider the needs of clinicians treating brain disease. Even more experts are poised to come on board, including drug development expert Dr John Villiger, who is helping to map out the path to clinic. “We are in a strong position to set up the infrastructure to drive therapeutics discovery for years to come. The next phase is making this pathway a permanent enabler of neuroscience research in New Zealand,” Flanagan says. “It’s exhilarating to think how quickly we could move from a billion molecules to finding one that could be developed into a drug.” And while the final answer may still be hidden somewhere in that vast chemical universe, the tools to find it are now firmly within reach. “Brain cells contain at least 20,000 proteins, and while we understand parts of the complex cellular pathways that cause inflammation, we do not know all the proteins involved,” Conole says. To track down the right targets in this ‘dark matter’, Conole uses special sticky molecules that block brain cell inflammatory responses, and a technique called precision mass spectrometry, to keep the research focused on the most important proteins. Funded by both the Neurological Foundation and the Hugh Green Foundation, Conole and Dragunow, as well as PhD student Raahul Sharma and post-doctoral fellow Dr Caitlin Oyagawa, uncovered new targets for neuroinflammation using this chemical biology approach, which will be further pursued in this Programme. “This work is important to making sure that we apply our digital screening approaches to the most relevant proteins,” Flanagan says. “Advances in AI technology to predict protein structure creates a really exciting opportunity to translate the outcomes of these chemical biology studies into the drug discovery pipeline.” Crossing the barrier Brain disease is notoriously difficult to treat, in large part due to the blood–brain barrier, which prevents viruses and infections from entering the brain, but also blocks most medicines. Even if the team find the one-in-a-billion molecule, it still needs to be delivered effectively to target brain tissue. “There has been no lack of research efforts to find a drug to cross the blood-brain barrier and stop neuroinflammation, but therapies that show promise in animal models often fail to translate effectively to clinical settings,” Dragunow says. When the in-vitro testing begins, a model of a blood- brain barrier grown from human brain cells is ready to go. The remarkable model is the result of two years’ work by Dr Rebecca Johnson, a Research Fellow and Neurological Foundation First Fellowship recipient, and Dragunow LabManager Sheryl Feng. Johnson says, “The tissue samples are donated to the Hugh Green Biobank from people with brain diseases undergoing neurosurgery at Auckland Hospital. A 3Dmodel, at atomic resolution, showing how one of 118 million compounds would behave inside a protein linked to neuroinflammation. The molecule is orange, and the blue area is where potential drugs can attach. The green structure shows another protein that works alongside it inside brain cells. “We’ve encountered a lot of complexity along the way. Humans are unique and every sample is variable.” Dr Rebecca Johnson “We are in a strong position to set up the infrastructure to drive therapeutics discovery for years to come. The next phase is making this pathway a permanent enabler of neuroscience research in New Zealand.” Associate Professor Jack Flanagan 14 Headlines 15 Headlines