Understanding the human body is central to medical research, but recreating its complexity in the laboratory is no simple task.
At the North-West University (NWU), researchers are developing human-based models that replicate aspects of human physiology and disease, potentially reducing the need for animal testing.
The research, led by Prof. Chrisna Gouws and her team at the Centre of Excellence for Pharmaceutical Sciences and the Desmond Tutu School of Medicine, forms part of Human-Based Biomedical Research and New Approach Methodologies (NAMs), using human data, cells, tissues and computational methods as alternatives to live animals.
“Human-based biomedical research prioritises human-relevant models and data to study human biology and diseases, while being more predictive for drug development,” says Prof. Gouws, a research professor.
“Modelling human physiology more accurately could promise faster, more accurate and cost-effective approaches to drug discovery and understanding human disease.”
Bringing human biology into the laboratory
Animal and non-animal methods both remain important in bioscience, Prof. Gouws stresses, but animal models have limitations.
Differences between animals and humans in anatomy, genetics and metabolism mean results do not always translate to people, contributing to the high failure rate of medicines entering clinical trials.
Traditional cell culture generally grows cells as a single layer on flat plastic, unlike the body’s three-dimensional environment, where cells interact with the extracellular matrix and are influenced by blood circulation, oxygen levels and communication between organs.
Using NAMs and tissue engineering, especially three-dimensional cell cultures, researchers can recreate some of this complexity.
“When using human cells, it is possible to mimic human disease mechanisms better because human genetics is present,” explains Prof. Gouws.
They can also incorporate more of the genetic and phenotypic variation found among human populations, which has historically been limited in animal models.
“But no laboratory model can reproduce every aspect of human biology,” cautions Prof. Gouws. “A model can be very representative of one mechanism while being a poor representation of another part of the biology.”
From human cells to mini tumours
At the NWU, the team has developed human cancer models for lung, colorectal, skin, breast, brain, liver and nasal epithelial cancers, as well as skin, airway, wound-healing and toxicity models.
The researchers are establishing cerebral organoids – “mini brain tissues” – from stem cells, with liver organoids and a full-thickness skin model planned.
The models can use human cell lines or induced pluripotent stem cells (iPSCs) – adult cells reprogrammed into a stem-cell-like state and then into the required cell type.
In some cases, researchers can also work directly with patient samples or biopsies, particularly in cancer research, to investigate an individual patient’s response to treatment.
“The goal is to create a platform for individual treatment screening for patients in the future,” says Prof. Gouws.
Large-scale testing is still some way off, she says. For now, the focus is on models representing specific functional effects, African genetic diversity and rare-disease patients.
Watching treatments work
The process starts with a model representing the disease or biological mechanism being investigated.
For a potential anti-cancer compound, cancer spheroids can be treated across varying concentrations and timeframes to measure effects on growth and viability.
This can eliminate compounds early if they lack efficacy or show unacceptable toxicity, or guide the choice of an animal model.
Researchers can take multiple samples from the same model or observe real-time intracellular signalling, which is difficult or impossible to achieve with animal models.
“We grow mini tumours in a bioreactor, and then treat them with various drugs or plant extracts over time,” says Prof. Gouws.
By monitoring tumour growth, viability and pathway markers, researchers can assess a treatment’s activity.
Other platforms, including microfluidic chip technology, can show how a tumour spreads into surrounding tissue or affects another organ.
The approach has been applied to Lessertia frutescens, commonly known as cancer bush.
“Using our 3D cancer models not only helped to standardise the way we tested the treatment, but also allowed us to treat for much longer periods of time than was previously possible,” says Prof. Gouws.
The team is also using 3D cancer spheroids to develop a cancer-bush-based complementary medicine for palliative cancer care.
Beyond cancer, the team is working with the NWU’s Centre for Human Metabolomics on rare-disease models for potential drug repurposing, as well as skin models for transdermal drug delivery and wound healing.
Bringing research closer to the people it benefits
The NWU has been working with three-dimensional cell culture since 2013, when the field was still in its infancy in Africa.
Since then, the university has built a human-based biomedical research cluster with cell-culture laboratories, 3D bioreactors, bioprinters and imaging facilities.
NAMs do not mean every form of animal research can immediately be replaced, says Prof. Gouws.
In biomedical testing areas such as systemic immune responses and reproductive health, suitable validated alternatives do not yet exist.
“Although for many the goal is complete replacement of animal testing, this is probably not achievable in the near future,” she explains.
The team’s goal is to reduce animal testing so that animal studies are used only where no suitable alternative exists.
But Prof. Gouws says South Africa still faces challenges in adopting these technologies, including cost, technical complexity, regulatory uncertainty and the need for greater standardisation and validation.
“For the NWU, the focus is not simply on replacing one laboratory technique with another,” says Prof. Gouws. “It’s on developing models that can answer questions about human biology more directly and bringing research closer to the people it benefits.”