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Researchers developing 3D cell culture models to advance drug discovery

11 July 2024 | Story André Damons | Photo supplied

FARMVOS — From top (left to right): Dr Angélique Lewies (researcher from the Robert WM Frater Cardiovascular Research Centre within the UFS Department of Cardiothoracic Surgery), Zurika Murray (behavioural geneticist from the UFS Department of Genetics), Dr Marieka Gryzenhout (C-rated scientist and Senior Lecturer in the Department of Genetics), and Dr Jaco Wentzel (serves as the pharmaceutical industry partner and consultant for the project at FARMOVS).

In an effort to advance drug discovery and disease research, researchers from the University of the Free State (UFS), the Central University of Technology (CUT), and FARMOVS, a clinical research company associated with the UFS, is developing innovative 3D cell culture models using 3D printed mini bioreactors.

This interdisciplinary project, led by Dr Angélique Lewies, researcher from the Robert WM Frater Cardiovascular Research Centre (Frater Centre) within the UFS Department of Cardiothoracic Surgery, is creating more accurate and human-like models for this purpose, reducing the need for animal testing, and improving the safety and effectiveness of new treatments.

The project was initiated to address the challenges associated with current 3D cell culture techniques, which are often expensive and complex. Recognising the need for a more cost-effective and user-friendly solution, the researchers embarked on this collaboration to develop a novel 3D cell culture system. By making these advanced techniques more accessible, the team aims to enhance the reliability of drug testing and significantly reduce the reliance on animal experiments. This innovative approach not only promises to cut costs but also promotes ethical research practices in the scientific community.

Dr Lewies, whose research specialises in cardio-oncology (relationship between cancer treatment and heart health), particularly in understanding and preventing damage to cardiac cells caused by chemotherapy, leads the cell biology aspects of the project, focusing on the cultivation of 3D cancer spheroid and organoid cultures.

According to her, the project focuses on creating 3D cell cultures, known as spheroids and organoids, that mimic human tissues more closely. These 3D models can improve the reliability of drug testing and reduce the need for animal experiments, aligning with the 3R principles: Reduction, Replacement, and Refinement.

Creating a versatile platform

“Traditional drug discovery and disease studies often rely on flat (2D) cell cultures and animal models. While animal models are essential for understanding disease and testing drug safety, they don't always predict how humans will respond, and their use raises ethical concerns.

“We aim to develop affordable and efficient 3D-printed mini bioreactors for growing these advanced cell cultures. These bioreactors will be designed to fit into existing cell culture labs, making them accessible to researchers. By leveraging the cutting-edge 3D printing technology at CUT's Centre for Rapid Prototyping and Manufacturing (CRPM), the team hopes to create a versatile platform for various research applications,” says Dr Lewies.

She is joined in this project by UFS colleagues; Zurika Murray, a behavioural geneticist, and her colleague from the Department of Genetics, Dr Marieka Gryzenhout, a C-rated scientist and Senior Lecturer. Dr Jaco Wentzel from FARMOVS. is also involved in the project. Dr Wentzel serves as the pharmaceutical industry partner and consultant for the project. With experience in cellular biology and pharmaceuticals, he ensures that the new 3D cell culture models meet industry standards and can be effectively used in drug development. Dr Wentzel’s role is crucial in bridging the gap between academic research and practical application in the pharmaceutical industry.

Goals

According to Dr Lewies, this project aims to create more accurate and ethical models for drug testing and improving the development of new treatments. By combining expertise from engineering, biology, and mycology, the team is set to revolutionise how diseases are studied, and medicines developed. Funded by the CUT and UFS Joint Research Programme, this initiative promises to foster innovation and lead to new research collaborations.

“Cardiac cell damage, known as cardiotoxicity, can lead to serious cardiovascular diseases and is a major reason why some drugs are removed from the market. By developing 3D cancer spheroids and cardiac organoids (mini heart models), my team aims to find ways to prevent this cardiotoxicity while enhancing the effectiveness of chemotherapy drugs.

“Additionally, they are exploring the cardiotoxic effects of natural products, such as medicinal plants and mushrooms, which show potential for both anticancer and cardio-protective properties,” says Dr Lewies.

Experts

Murray is interested in how the psychedelic compounds psilocybin and psilocin affect the brain with her research focusing on the epigenome of genes within the serotonin pathway, which could explain the therapeutic potential of these compounds. “As part of this project, Murray will work with the Frater Centre to develop neuronal organoids (mini brain models) using the 3D mini-bioreactor platform.

“This will allow her to investigate the effects of psilocybin and psilocin on brain function, which have shown promise in treating mental health disorders like depression and anxiety, aiming to understand how these substances might help treat mental health issues,” says Dr Lewies.

Dr Gryzenhout brings her expertise in mycology and is responsible for cultivating medicinal mushrooms used in the project. Dr Gryzenhout's research focuses on the genetic characterisation of medicinal mushrooms and evaluating their therapeutic potential. These mushrooms produce a variety of bioactive compounds with therapeutic benefits, including anticancer activities, heart protection, and immune system support.

Her team is also approved by the South African Health Products Regulatory Authority (SAHPRA) to research the controlled psychedelic compounds psilocybin and psilocin.

Drug Discovery Goals

The project’s long-term focus is on potentially discovering new drugs to prevent and treat heart and brain diseases. Specifically, the team is working on developing therapies for cardio-oncology and neurological applications. In the realm of cardio-oncology, the goal is to find treatments that prevent cardiac cell damage and downstream cardiovascular diseases caused by cancer therapies, while still effectively targeting cancer cells. For neurological applications, the researchers are exploring the potential of drugs derived from medicinal mushrooms, including those with psychedelic properties, to treat conditions like depression, anxiety, and other mental health disorders.

News Archive

Research by experts published in Nature

2011-06-02

The members of the research group are, from the left, front: Christelle van Rooyen, Mariana Erasmus, Prof. Esta van Heerden; back: Armand Bester and Prof. Derek Litthauer.
Photo: Gerhard Louw

A research article on the work by a team of experts at our university, under the leadership of Prof. Esta van Heerden, and counterparts in Belgium and the USA has been published in the distinguished academic journal Nature today (Thursday, 2 June 2011).

The article – Nematoda from the terrestrial deep subsurface of South Africa – sheds more light on life in the form of a small worm living under extreme conditions in deep hot mines. It was discovered 1,3 km under the surface of the earth in the Beatrix Goldmine close to Welkom and is the first multi-cellular organism that was found so far beneath the surface of the earth. The worm (nematode) was found in between a rock face that is between 3 000 and 12 000 years old.

The research can shed some new light on the possibility of life on other planets, previously considered impossible under extreme conditions. It also expands the possibilities into new areas where new organisms may be found.

These small invertebrates live in terrestrial soil subjected to stress almost for 24 hours They live through sunshine, rain, scorching temperatures and freezing conditions. Through time they developed a means to cope with harsh conditions. Terrestrial nematodes (roundworms, not to be confused or related to earthworms) are among those very tough small invertebrates that deal with those conditions everywhere. After insects they are the most dominant multi-cellular (metazoan) species on the planet having a general size of 0,5 to 1 mm and are among the oldest metazoans on the planet, Nature says in a statement on the article.

They inhabit nearly every imaginable habitat form the deep seas to the acid in pitcher . Some nematodes simply eat bacteria and these are the ones we study here. Terrestrial nematodes have developed a survival stage that can take them through hard times (absence of food, extreme temperatures, too little oxygen, crowding, and more).

At the head of the research was Prof. Gaetan Borgonie of the Ghent University in Belgium and a world leader in the discipline of nematode research. He was brought into contact with the South African research leader, Prof. Esta van Heerden, who set up a cooperation agreement with the University of Ghent and Prof. Borgonie. Prof. Van Heerden manages the Extreme Biochemistry group at the UFS and the research was funded by several research grants.

The search for worms began in earnest in 2007, but it was soon clear that the sampling strategy was insufficient. A massive sampling campaign in 2008-2009 in several mines led to the discovery of several nematodes and the new nematode species Halicephalobus mephisto. It is named after the legend of Faust where the devil, also known as the lord of the underworld is called Mephistopheles.

Nature says special filters had to be designed and installed on various boreholes. Unfortunately, there is no easy way of finding a magic formula and designs had to be adapted by trial and error; improving existing designs all the time. The work of the UFS Mechanical Workshop, which manufactured, adapted and helped design it, was crucial in this respect. Filters were left on the holes for varying periods, sometimes for a few hours and sometimes for months. Prof. Derek Litthauer from the UFS played a big role in sampling, filter designs and coming up with ideas for names for the new nematode with Prof. Borgonie.

Research showed that the nematodes can live in the deep for up to 12 000 years. Three students – Armand Bester, Mariana Erasmus and Christelle van Rooyen from the UFS – did the work on this.

The importance of multi-cellular animals living in the ultra-deep subsurface is twofold: The nematodes graze on the existing bacterial population and influence their turnover. Secondly, if more complex multi-cellular organisms can survive in the deep subsurface on earth, this may be good news when looking for life on other planets where the surface is considered too inhospitable (e.g. Mars). Complex life forms can be found in ecosystems previously thought to be uninhabitable. Nature says this expands the possibilities into new areas where new organisms may be discovered.

Future research will focus on selective boreholes to look for more metazoans, so that a better idea of the complexity of the ecosystems there can be obtained. It will also look for metazoans in the deep subsurface on other continents to determine similarities and differences.

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