Professor Wai-Hong Tham was one of four distinguished female researchers to receive 2022 NHMRC Elizabeth Blackburn Investigator Grant Awards. Her award was for the highest ranked female recipient (Leadership category) in the Basic Science research area of the Investigator Grants scheme. Professor Tham is Head of the division of Infectious Diseases and Immune Defence at WEHI and co-Chair of the WEHI Biologics Initiative.
Read on to find out more about the motivations behind Professor Tham’s research, and what she is planning on achieving with her Investigator Grant, in her own words.
Infectious diseases have been potent factors in shaping human evolution and human history, killing millions across the millennia. The COVID-19 pandemic was a powerful reminder for the first time in a century of the potential global impact of a highly infectious illness. Additionally, the global distribution and spread of infectious diseases, especially those borne by insects and water, are very likely to be affected by accelerating climate change.
Growing up in Malaysia, I still remember the smell of mosquito coils and emptying water retaining containers after the rains and could see the impact of infectious diseases, particularly malaria and dengue. Malaria cases in Australia annually number in the hundreds, but around the world as many as 600,000 people die from malaria every year. Devastatingly, the most vulnerable group are children under five years of age.
Malaria is a truly ancient disease so, as a biologist, I found it fascinating that many of the fundamental processes by which Plasmodium parasites enter human cells were not well known or understood. That is where my research has been focused in recent years: understanding host-pathogen interactions at structural and molecular levels so that we can develop more focused interventions.
Monoclonal antibodies have become treatments of choice for many cancers and inflammatory diseases, but only a handful of antibody therapeutics have so far been licensed for treatment of infectious diseases. Thanks to recent innovations in antibody engineering and delivery, we have the potential to revolutionise the treatment and prevention of infectious diseases if we can identify optimal pathogen targets to stop the cycle of infection.
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In my lab, we have focused on new antibody-based therapies that [protect] against malaria and COVID-19. We have established the first immunised alpaca nanobody platform in Australia. Alpacas make unique antibodies, smaller than human antibodies, which we use as the basis for laboratory-made antibody fragments called “nanobodies” that recognise foreign proteins. Our approach is to combine diverse antibody modalities with advanced structural approaches such as X-ray crystallography and cryogenic electron microscopy to drive the rational design of the most potent and effective antibody therapy.
Over the coming five years, our malaria research will continue to build our in-depth understanding of the protein complexes that are critical to parasite fertilisation, so we can target them as antigens using novel antibody-based and nanobody-based interventions. Malaria parasite fertilisation occurs within the mid-gut of the female Anopheles mosquito, so by stopping fertilisation you can stop the transmission of the parasite from mosquitoes to humans.
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As COVID-19 emerged, we were also able to use approaches developed from our work on malaria to help produce potent nanobodies against spike proteins to prevent virus entry. In the next phase of research, we will further develop our potent nanobody cocktail by exploring different formulations and routes of administration to allow cheaper and easier administration of antibody-based therapies to the site of COVID-19 infection.
Of the seven coronaviruses that infect humans, three are already associated with epidemic and pandemic infections: severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and COVID-19. To prepare against the risk of future human coronavirus pandemics, we will be generating collections of nanobodies that block viral entry of all human coronaviruses.
Our work has the potential to understand fundamental biology of malaria parasite sexual stages and to generate antibody therapeutics for malaria and human coronaviruses, using antibody discovery platforms coupled with advanced technologies in structural biology. In the future, we hope that this work ultimately informs new therapeutics against infectious diseases.
My successful career in research has been driven to some extent, I think, by my own need for variety, working in plant biology, telomere silencing, meiotic segregation to finally infectious diseases. Every few years, I have taken up opportunities to change direction, to learn and apply new techniques, or to apply knowledge from an existing area to a new one. I encourage young researchers to try to work at the edge of their knowledge, to embrace challenge and change. For me, that is what keeps research exhilarating as well as life-changing.
Read more about NHMRC's Research Excellence and Biennial Award recipients in our media release.