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The behind the scenes story of discovering life saving drugs

Authors:
Xiaoyu Wu – School of Engineering and Built Environment, Griffith University
Benjamin Lu – MacGregor State High School
Tristan Fletcher – MacGregor State High School

Have you ever wondered how all the medicines you see at the pharmacy came to be there? These tiny tablets can seem magical in how they can save lives and improve quality of life. However, these great pills owe much to science.

All of these medicines have gone through a long, complex scientific process in order to determine their effectiveness, safety and long-term effects in humans. At the forefront of this drug development process is Professor Vicky Avery and her team in Discovery Biology at the Griffith Institute for Drug Discovery, Griffith University. Prof. Avery’s team help find treatments for cancers and infectious diseases such as malaria and Chagas disease. But how does her team do their work?

Drugs are small chemicals, also known as compounds, that have been designed to interfere with the biological processes that allow diseases to occur. Prof. Avery’s team find compounds that specifically interfere with diseases whilst not harming their hosts. The team play an integral role in the in vitro or ‘test tube experiment’ first stage of drug discovery that allows compounds that selectively and effectively target diseases to be found. Once given a disease target to study, Prof. Avery and her team design experiments or ‘assays’ that allow them to undertake ‘high throughput screens’ that involve thousands of compounds being rapidly tested against diseased cells, such as those found in cancers, or harmful microbes that can cause illnesses.

Of course, we can’t give potentially dangerous compounds to humans, so replicating and growing diseased cells or microbes in vitro allows for their testing outside of humans. To achieve this, Prof. Avery’s team must first make a large number of identical copies of the diseased cells or infectious organisms so that the potential medicines can be tested.

The diseased cells or microbes must be maintained as healthy as possible before use and the compounds need to be evaluated within identical environments so that the experiments are reproducible and accurate. Plus, the causation relationship is tough to prove so testing conditions need to be strict, with numerous controls. It is also important that the experiments imitate what is happening in humans, so as to maximise the chance that the compound can go from the in vitro stage to being tested in animals, then further still to being used as a medicine in humans.

Drug discovery is also a costly and time-consuming activity. Prof. Avery’s team runs at a budget of millions of dollars per year. Thus, ensuring the effectiveness of candidate compounds at an early stage is essential to both saving people’s lives and ensuring efficiency during the discovery process, as it is vital to not waste money and time on candidates that will not perform well in the later stages of the drug discovery and development pipeline.

“We provide biologically and physiologically relevant assays to mimic the disease and thus improve translation of outcomes from in vitro (in the laboratory) to clinic. The more relevant our assays are, the higher the likelihood that the compounds we identify will be acting through mechanisms that occur in the body, thus there is greater potential for these molecules to be successful and progress to the clinic,” said Prof. Avery.

To undertake a high throughput screen, Prof. Avery’s team start off by first setting up their assays in micro-titre plates that are like thousands of miniature test tubes or wells with identical environments, each containing the same amount of the targeted disease cells or organism. Next, they add different compounds to each well, and after incubating them together to allow the compounds to have their effect, they use sophisticated automated imaging systems to take images to determine how effective the compounds have been on preventing the cells or organisms from growing or behaving in a certain manner. They can determine whether there are any changes in the diseased cells’ or microbes’ shape, size, or specific markers that would indicate that a compound has had an effect.

To achieve this, Prof. Avery’s team have two essential helpers. State-of-the-art robots coupled with automated imaging machines allow for the rapid testing and screening of the compounds to determine their effect on cells or organisms. The team also have access to an extensive library of compounds, with screens being undertaken on sets of 5,000 to 30,000 compounds at a time.

Once a compound candidate is identified, Prof. Avery’s team run several retests to make sure the results weren’t a false positive and that the candidate is performing as it was designed to. Once they have compounds with validated activity, the process of optimising the compounds begins. The compounds are subjected to medicinal chemistry to further improve their effectiveness and reduce any potential side effects. Following each modification, Prof. Avery and her team test the activity of the new compounds.

“My team and I work with academic groups, industry and not-for profit organisations. We have contributed to drug discovery efforts for multiple different cancers, malaria, Chagas disease, leishmania, African sleeping sickness, asthma, gastrointestinal diseases, bacterial infections, autoimmune diseases and many more. It is rewarding to be able to do research that progresses the discovery of new treatments for a range of diseases,” said Prof. Avery.

The road to a drug becoming available on pharmacy shelves is long, hard and expensive. Prof. Avery and her team play an important role in not just the initial identification of compounds with the potential to become drugs, but ensuring that they will have the best chance of getting through all the trials associated with drug development. The team’s expertise can be applied to finding treatments for a number of diseases, and highlights the importance of reproducible and robust scientific methods.

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