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Organs-in-a-dish aid drug discovery

Using stem cells to generate complex tissues and organs in the lab is promising to tackle a key bottleneck in drug discovery
Artificial organs tissues people

In the seminal movie Blade Runner, director Ridley Scott brought to life a world in which the creation of tissues and organs - and even artificial people - was commonplace.

For its time - it was released in 1982, 18 years before the first draft of the human genome was released and 14 years before the cloning of Dolly the sheep - Blade Runner was remarkably prescient about the future direction of genetic engineering, and the ethical dilemmas posed by the technology. 

More than 30 years later the promise of being able to shop for genetically identical, replacement body parts remains the stuff of science fiction, but the first steps down that road are already being taken.

The last few years have seen significant stride forwards in the use of induced pluripotent stem cells (IPSCs) to grow complex tissues and organs in cell culture that - while imperfect - are starting to exhibit the structure and function of their natural counterparts.

Since 2008 researchers around the world have created three-dimensional cellular structures that serve as primitive versions of body parts such as the brain, kidney, liver, pancreas, retina, trachea, and most recently the intestines.

Selected milestones in organoid development

RIKEN Institute team stimulate neural cells to form clusters with organised layers
Hubrecht Institute shows intestinal stem cells can form organoids
University of Pittsburgh researchers devise a 3D system in laboratory culture that mimics the growth patterns of colon cancer stem cells
US doctors implant an artificial trachea grown from a cancer patient's own stem cells
Mario Negri Institute for Pharmacological Research team creates renal organoids that retain some functions when implanted into animals
Institute of Molecular Biotechnology of the Austrian Academy of Science create model brains with some of the complex structures of the organ
A group from Yokohama grow a crude liver from stem cells taken from skin
Stem cells are coaxed into forming mushroom-shaped buds which mimic the structure of the kidney by scientists at the Salk Institute for Biological Studies
A University of Copenhagen team grow tree-like structures using pancreatic cells
Scientists from Cincinnati Children's Hospital Medical Center create the first functional human intestinal tissue from stem cells

The potential for medicinal breakthroughs is clear. To give just one oft-cited example, the creation of pancreatic organoids that could react properly to blood glucose levels might be able to restore a degree of insulin function when transplanted into diabetic patients.

More immediately, however, the technology promise to have a dramatic impact on pharmaceutical R&D. Drugmakers have become incredibly efficient at generating and screening compounds for drug discovery, but the rate of attrition when leads start clinical trials remains stubbornly high.

One of the primary reasons for this bottleneck in the R&D pipeline is believed to be that the assays used to test activity against a drug target tend to involve isolated cells – in other words a two-dimensional (2D) system that is a poor reflection of the three-dimensional (3D) environment within the human body.

Replacing 2D cell culture with 3D organoids or 'proto-organs' could also reduce the number of animals required by regulatory authorities for validation of new compounds before they proceed to clinical trials, another expensive component of the drug discovery pathway that in reality often fails due to fundamental differences between human and animal model physiology, according to stem cell researchers Adrian Ranga, Nikolche Gjorevski, and Matthias Lutolf of the Ecole Polytechnique Fédérale de Lausanne (EPFL) in Switzerland.

Writing recently in the journal Advanced Drug Delivery Reviews (ADDR), the scientists note that by 'recapitulating not only the form but also the rudiments of function of their in vivo counterparts, [organoid] constructs have the potential to move from laboratory proof-of-concepts to relevant tools in the drug discovery pipeline'.

They can provide the 'missing link' between compound screening and clinical trials and serve as models for testing not only the efficacy of a drug in its target organ, but also other characteristics such as its toxicity to the liver or bioavailability in the gastrointestinal tract, they conclude.

In October, researchers from Cincinnati Children's Hospital Medical Center in the US reported in Nature Medicine the successful creation of functional intestinal tissue in the lab for the first time, using IPSCs from adult skin and blood samples that were stimulated with growth factors to encourage them to develop into intestinal cells.

The resulting organoids were shown to develop and mature when transplanted into mice genetically engineered to host human tissue without causing an immune response. They were comprised of differentiated cells in the mucosal lining and muscle layers and were able to carry out digestive functions, such as taking up nutrients.

“These studies support the concept that patient-specific cells can be used to grow intestine,” said lead investigator Michael Helmrath.

In time patients could receive transplants of tissue derived from their own stem cells to treat “diseases and conditions that can cause intestinal failure”, he added, but in the meantime using the tissue in place of conventional drug screening and animal testing “could shave years off the drug development process”. 

There are even suggestions that in the future multiple organoids could be combined to create a complex system - a 'human-in-a-dish' if you will - that would be even closer to the environment within the body.

Toxicity testing

Researchers David Grainger and Anna Astashkina of the University of Utah in the US also report in ADDR how drug failure due to toxicity indicators “remains among the primary reasons for staggering drug attrition rates during clinical studies and post-marketing surveillance”.

The creation of 3D liver organoids “have been among the greatest successes of 3D organoid culture systems in terms of toxicity predictions invitro”, they note, adding that even simple liver 'spheroids' can provide valuable information on liver-specific metabolism and toxicity.

There are still serious limitations to the approach, however, not least that there is no agreed method of extrapolating human dose information from these invitro studies, as well as the inherent difficulties in manipulating growth conditions to reliably scale up the use of organoids to allow high-throughput screening.

Nevertheless, the promise of the technology is clear, according to Meritxell Huch from Cambridge University's Gurdon Institute, who won the UK National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) 3Rs Prize earlier this year for her work on growing liver organoids from adult mouse stem cells.

“Typically a study to investigate one potential drug compound to treat one form of liver disease would require up to 50 live animals per experiment, so testing 1,000 compounds would need 50,000 mice,” said Huch.

“By using the liver culture system I developed, we can test 1,000 compounds using cells that come from only one mouse, resulting in a significant reduction in animal use.”

Disease models

Meanwhile, scientists are increasingly using organoid approaches to create models of diseased tissue, particularly malignant tumours, and a number of groups have described how the models give notably different drug responses compared to 2D cell culture. In time, tumour responses to therapies could be assessed not only in isolated organoid cultures, but also in a more realistic scenario where they are implanted within a living organism.

In September, researchers reported in Cell4 how they created prostate cancer organoids from circulating tumour cells that retained the same characteristics of tumours in patients.

The achievement could overcome a major obstacle in prostate cancer research, namely the lack of an invitro model that “recapitulates the diversity” of the human disease, according to the researchers, led by Yu Chen of Memorial Sloan Kettering Cancer Center in the US.

“By developing these organoids from patient prostate cancer samples, we are able to study the tumours in greater detail and correlate the genetic mutations with the response to various drugs,” he said.

Regardless of the promise, use of the models in drug discovery remains in its infancy, according to Lutolf.

“The wider implementation of these bio-mimicking approaches within the drug development community will require the level of reproducibility and consistency currently achieved with cell lines,” they note in the ADDR review.

Article by
Phil Taylor

is a freelance journalist specialising in the pharmaceutical industry

6th January 2015

From: Research, Healthcare



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