Bio21 Guest Message - 22 May 2020 - Professor Phil Batterham
Speaking at a dinner to mark the opening of the Bio21 Institute the then Chancellor of the University of Melbourne, Ian Renard AM, drew parallels between the quality and diversity of research activities to be conducted in the new Institute and the joy of taking in the culinary delights of the many great cafes lining Brunswick Street. This comparison prompted me to smile knowingly because, even in those very early days, the point that Ian was making was already resonating with my experience. Walking the corridors of Bio21, I sensed the creativity and energy emanating from the great labs that populate the Institute. Back then it was a new and fresh experience. I only knew my colleagues by reputation, but over time I have come to understand the quality of the research upon which those reputations are based. More than that, I have reaped the benefits of generous collegiality. In this article I speak of my personal experience, not because it is in any way unique. It is not, but it does serve to exemplify the way in which adding different research perspectives and skills to a research program can totally transform what is achievable. There is a purpose to telling this story.
My research focuses on insecticides. For most part I have conducted research on how these chemicals kill insect pests and the genetic/biochemical mechanisms that evolve to confer resistance to them. In more recent times I have focused on what low doses of insecticides might be doing to contribute to the massive declines in insect populations that are being observed around the world. Given the constant threat insect pests pose to our agricultural yields and the dependence of our agriculture on beneficial insects (e.g. honeybees), this research is of some significance.
Quoting Dirty Harry, ‘a man’s got to know his limitations’. In tackling such a complex web of research questions, I have been aware of mine. Insecticides are chemicals. I know almost nothing about chemistry. Insecticides bind to proteins. I know almost nothing about protein structure and function. Insecticides trigger a cascade of metabolic and behavioural impacts. You’ve guessed it. I know nothing about…. But in Bio21 I have established collaborations (which I view as research friendships) with outstanding researchers who have complementary skills. Together we have forged a formidable team capable of addressing my significant research questions, holistically and powerfully.
Entering the Bio21 Institute my lab worked on several insecticides with a focus on two, the world’s top selling insecticide, imidacloprid and an organic alternative, spinosad. As a PhD student, Trent Perry, had shown that these insecticides target different nicotinic acetylcholine receptors (nAChRs). Other postgraduate students were working on the characterization of two large gene families, the cytochrome P450s and the glutathione-s-transferases (GSTs), members of which are involved in insecticide detoxification. In those days Michael Parker, although based at St Vincent’s Institute, was working one day a week in an office a few doors down from mine. Stopping by for a chat, I discovered that Michael’s broad research interests embraced the GSTs and the ligand gated channel proteins that included the nAChRs. Shortly after that chat Michael’s lab began to provide significant research support, modelling how imidacloprid might bind to its nAChR target and producing a crystal structure for a GST implicated in insecticide resistance, GSTD1. Paul Gooley and Malcolm McConville volunteered their assistance to a PhD student, Lloyd Low, who was working on the GSTD1 enzyme, using NMR and mass spectrometry to show precisely how DDT binds to the enzyme and to detect the metabolites produced. In more recent years Wei-Kai Chen from my group has found evidence that GSTD1 may have a role in regulating the insect xenobiotic response and Michael Parker’s lab has again entered this story, assisting Kai to examine the protein-protein interactions that may underpin this response. Meanwhile Tracy Nero from the Parker lab has been assisting my PhD student, Alex Giang, to understand the structural distinctives that allow the P450 CYP6G1 to metabolize imidacloprid.
While insecticide resistance is often caused by an enhanced capacity metabolism, the methods available to identify the metabolites were laborious and insensitive. I had discussed this problem with Richard O’Hair. Years later, Richard O’Hair knocked on my office door to tell me that he had a postdoc and an MSc student that would work with my lab to develop a method to detect the metabolites of imidacloprid. They were successful in this endeavour and a PhD student co-supervised by Richard and I, Roberto Fusetto, subsequently used this twin ion method of mass spectrometry to show how the metabolism of imidacloprid leads to resistance.
Over the last few years my work has branched out to look at the impact of low doses of the insecticides, imidacloprid and spinosad, on non-pest insects. This research, spearheaded by PhD student, Felipe Martelli, has been prompted by evidence that insecticide use could be contributing to the sharp decline in insect population sizes. Imidacloprid has been associated with the colony collapse phenomenon in honeybees. In this research we have received great support from Ute Roessner (School of BioSciences) and members of the Metabolomics Australia team in examining the way insecticides perturb the lipidome and metabolome. This has been central to demonstrating that insecticides cause an increase in oxidative stress that precipitates a series of downstream impacts including neurodegeneration.
There have been so many conversations and interventions by Bio21 colleagues that have empowered my research. Some of the great ideas and support offered will nucleate future research. I am deeply grateful for the fact that over a period of 15 years, every time I have sought support from a Bio21 colleague the response has been an enthusiastic ‘yes’.
Most research problems in biology and medicine are multidisciplinary, requiring a diversity of expertise and technologies in order to be fully addressed. My story is but one example of the truth of that statement. Whether in challenging times, such as those being encountered during the Covid-19 pandemic, or in easier times pooling expertise and resources is the best way forward. I encourage my colleagues within Bio21 to keep on exploring the breadth of talent and the value of the platform technologies that exist within the Institute. For researchers outside, you may want explore Bio21 as I have done, seeking empowering complementary expertise.
Professor Phil Batterham
School of Biosciences
Faculty of Science
Bio21 Institute
