How 3D biology is informing drug discovery

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DDW Editor Reece Armstrong looks at the advantages and opportunities 3D cell cultures, organoids and stem cells are bringing to drug discovery teams.

The use of 2D biology in the pharmaceutical industry has provided researchers with ways to observe how cells react to different drug compounds and has helped inform drug discovery and development strategies for decades. 2D biology – a cell culture grown in-vitro – have been essential to understanding mechanisms of diseases for years but they face limitations which have potentially restricted the rate of drug discovery and development. Perhaps the biggest limitation is that 2D cell cultures do not properly reflect the actual biology of how cells behave – within a 3D environment in the body – and as such, lack the cell-cell interactions which can help us better understand how diseases operate and how molecules interact with disease targets.

Enter 3D biology

3D biology has emerged as somewhat of a successor to 2D biology. Whilst the former still has its uses and applications, research into 3D biology has blossomed, with many now considering the transition to this technology.

Some advantages of 3D biology include:

  • More relevant cell models compared with 2D cell cultures
  • Reduces the use of animal models
  • Better predictors of efficacy and toxicity
  • Cell-to-cell interactions can inform how diseases and drugs work in the body

What is 3D biology?

Unlike 2D biology, in which cell cultures are grown in flat petri dishes, 3D biology uses techniques that enable in vivo like cell culture conditions that better mimic how cells act within the body. This is done using either a scaffold-based approach, in which hydrogels are used to support cells grown in a 3D environment, or scaffold free techniques such as magnetic 3D cell cultures, in which cells are magnetised and directed together to be formed into spheroid or layered 3D structure.

The move towards these types of 3D biology has grown in recent years. According to MarketsandMarkets, the 3D biology sector was valued at $1.3 billion in 2023, and is expected to reach $2.5 billion by 20281. This trajectory is understandable when research papers into the use of 3D cell cultures have grown so significantly. Within the last 10 years the number of yearly research papers focused on 3D cell cultures has grown well past 1,000.2 Speaking about the growth of 3D cell culture, Kenan Moss, Application Specialist at PHC, says: “While traditional 2D, or monolayer, cell cultures are widely used and have had decades of characterization, it’s always been known that there are limitations in its use as an in vitro model of cell growth and actual cell processes. By adding the cell-cell interactions and intercellular signalling that comes with the architecture of 3D cell culture, we can gain new insight into the age-old field of cell culture. 3D cell culture helps researchers build more complex cell culture models that better represent actual in vivo conditions.”

Moss’ comments hit on one of the biggest challenges scientists face within drug discovery and development – that of translational failure, in other words, where results seen within animal studies do not translate into humans. In fact, the rate of failure in the pharmaceutical industry for drugs within clinical trials is as high as 90%3 indicating that the sector needs to improve aspects of target validation and candidate selection or drug optimisation.

Since 3D cell cultures offer a more representative model of how cells operate within the body, and how molecules perform on them, there’s the potential that these technologies can offer either an alternative to animal testing, or act as an intermediary to confirm results seen in animal studies. As such, 3D biology could present a way to bridge the gap between in vitro and in vivo. Indeed, the fact that 3D cell cultures can provide a more relevant human platform for researchers to test upon, allows them to better predict aspects such as efficacy and toxicity and potentially reduce or confirm animal studies and their results.

This growth in 3D biology is something that regulatory bodies are now strongly considering, and agencies have started encouraging pharmaceutical developers to use available technologies. For example, the FDA’s Predictive Toxicology Roadmap considers how advanced in vitro models might be able to improve the accuracy of toxicology testing. Additionally, the FDA Modernization Act 2.0 signed by President Biden in 2022, encourages alternatives to animal testing, including the use the cell-based assays, 3D cell cultures, organoids, human induced pluripotent stem cells (iPSCs) and more. The signing of the act indicates a growing consensus of a necessity to move away from previous testing models and towards models that offer a better chance of therapies making it to market and ultimately patients.

Organoids

Organoids exist as a research tool within the field of 3D biology and offer enhanced modelling of human tissues. Organoids are derived from stem cells and are designed to mimic the structure and functions of human organs. Since they’re derived from stell cells, organoids can be differentiated into a range a tissue types and offer researchers a platform to better understand disease development.

One recent advance this year saw researchers from the University of Michigan develop a way to produce human brain organoids without animal cells. The development could pave the way for improvements in how neurodegenerative conditions are studied and treated.

The researchers intended to overcome weaknesses in the substance traditionally used to make the extracellular matrices in brain organoids, known as Matrigel. They developed a novel culture method that uses an engineered extracellular matrix for human brain organoids – without the presence of animal components – and enhanced the neurogenesis of brain organoids compared to previous studies.

The team used human fibronectin, a protein that serves as a native structure for stem cells to adhere, differentiate and mature, as the foundations of the extracellular matrices. The team used proteomics to assess the organoids, finding that the brain models developed cerebral spinal fluid (CSF), which more closely matched human adult CSF compared to human brain organoids developed in Matrigel.

When asked about how organoids can help analyse diseases and develop therapies, Moss comments: “Many cell lines traditionally grown in 2D don’t actually grow as monolayers in vivo, thus treatments and therapies that are tested in vitro on the kinds of 2D models can’t always be relied on to behave similarly, or as effectively in live trials. 3D cultures, in there varying forms, get us a step (or many steps) closer to more efficient in vitro models that better mimic in vivo specimens.”

Organoids are now being used across various fields of research and are ideal for understanding how diseases primarily affect singular organs.

In terms of the opportunities for drug discovery and development, Moss explains: “Cell-cell interactions between anomalous cells (e.g. cancerous, infected, genetically damaged, etc) and between anomalous cells and healthy cells have always been known to impact disease progression and treatment efficacy. Organoids provide many of the conditions of the extracellular environment of interest necessary to model and test drug treatments and therapies. This in turn will help researchers better estimate the impact these treatments would have on patient condition in vivo.”

Stem cells

Stem cells have much use across drug discovery and development. They serve as great vehicles for researchers to understand cell biology, differentiation enables them to be programmed into specialised cell types, and the therapeutical potentials of stem cells is something that has excited and alarmed the industry for years now.

As with 2D biology, stem cells have primarily been cultured using common culture methods in flat, plastic petri dishes that aren’t representative of true human physiological conditions.

Stem cells’ use in the development of organoids is one example of how they’re currently being utilised within 3D biology.

Eva Feldman, Director of the ALS Center of Excellence at U-M and James W Albers Distinguished Professor of Neurology at U-M Medical School explains: “There is a possibility to take the stem cells from a patient with a condition such as ALS or Alzheimer’s and, essentially, build an avatar mini brain of that patient to investigate possible treatments or model how their disease will progress.”

“These models would create another avenue to predict disease and study treatment on a personalised level for conditions that often vary greatly from person to person,” Feldman adds.

On a treatment level, advances have been made too.

“There have been great strides in using stem cells – either iPS or embryonic – to halt or even treat genetic conditions that previously had no treatments. Stem cell implants can be used to introduce a new population of healthy cells into patients with conditions that cause disrupted cell activity,” Moss says.

A recent example of this comes from research from the University of Cambridge and the University of Milano-Bicocca, with an early-stage clinical trial showing how stem cell therapy for multiple sclerosis (MS) could prevent further damage to the brain. Whilst only a small study, the team is excited about the possibilities the results showed. During the study, the researchers injected between 5m and 24m neural stem cells directly into the brains of 15 patients with secondary progressive MS. The stem cells are thought to reduce the inflammation that drives the disease. During a 12-month follow-up, the therapy was well tolerated.

Another example comes from the recent approval by the Medicines and Healthcare products Regulatory Agency (MHRA) of the world’s first gene therapy for sickle-cell disease (SCD) and transfusion- dependent β-thalassemia (TDT).

Sickle cell disease and β-thalassemia are genetic conditions caused by errors in the genes for haemoglobin, which is used by red blood cells to carry oxygen around the body.

The treatment, Casgevy is the first medicine to be licensed that uses CRISPR to edit faulty genes in patient’s bone marrow stem cells so that the body goes on to produce functioning haemoglobin. To do this, stem cells are taken out of bone marrow, edited in a laboratory and then infused back into the patient after which the results have the potential to be life-long. Speaking about the approval decision, Julian Beach, Interim Executive Director of Healthcare Quality and Access at the MHRA says: “Both sickle cell disease and β-thalassemia are painful, life-long conditions that in some cases can be fatal. To date, a bone marrow transplant – which must come from a closely matched donor and carries a risk of rejection – has been the only permanent treatment option.

“I am pleased to announce that we have authorised an innovative and first-of-its-kind gene-editing treatment called Casgevy, which in trials has been found to restore healthy haemoglobin production in the majority of participants with sickle-cell disease and transfusion-dependent β -thalassaemia, relieving the symptoms of disease.”

DDW Volume 25 – Issue 1, Winter 2023/2024

References:

  1. https://www.marketsandmarkets. com/Market-Reports/3d-cell-culture- market-191072847.html
  2. https://www.researchgate.net/ figure/Number-of-publications- per-year-1968-2020-on-3D-cell- cultures-gathered-from-PubMed_ fig1_339746633
  3. Sun D, Gao W, Hu H, Zhou S. Why 90% of clinical drug development fails and how to improve it? Acta Pharm Sin B. 2022 Jul;12(7):3049-3062.

Reece ArmstrongAbout the author

Reece Armstrong is Editor of DDW. He has worked in life sciences and pharmaceutical B2B publishing for seven years and was previously Editor of European Pharmaceutical Manufacturer. He has a master’s degree in Journalism from Newcastle University.

 

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