News Article

Organoids are small. Their future is big.

February 22, 2024
Colorectal cancer organoids

“Much of our work has been focused on making the process of culturing organoids consistent, reliable and simple, all at a lower cost that makes scaling it up possible.”

-Shantanu Dhamija, VP, Strategy & Innovation at Molecular Devices 

In 2011, during a small clinical trial for a hepatitis B combination therapy, a patient suddenly died of multiorgan failure. It was shocking: Each therapy used as part of the combination had repeatedly been shown to be safe in humans, and laboratory testing had given no indication of severe risk. Yet an all-too-common side effect known as drug-induced liver injury (DILI) – which can range from mildly symptomatic to fatal—was ultimately found in all seven patients in the trial, including the one who died.  

In short, it was impossible to know whether this new therapy would be safe for real patients—until it was too late.  

The trial was immediately stopped, but DILI’s vast and unpredictable impact still looms large. More than 20% of clinical trials fail due to drug-induced liver injury, leading to as much as $3 billion annually in lost R&D drug development effort. 

Now, another toxicity screening method is on the rise: one that models not just individual cells but their structure as part of an organ. Human microphysiological systems, or “organoids,” can offer insights that two-dimensional cell models and animal testing can’t. Could organoids have seen DILI coming and saved this patient’s life?

The beauty and challenge of complexity

The dream of creating an “organ in a dish” dates back to 1907, when Henry Van Peters Wilson first demonstrated that dissociated sponge cells could reorganize into an entire organism. But over 100 years passed before researchers successfully modeled intestinal tissue using adult stem cells and the field of organoid development was off to the races. For the first time, these tiny 3D structures were able to recreate the functional structures of an organ, essentially becoming mini-guts, mini-brains or mini-livers. 

Today, organoid research has become a key method for studying the underlying processes of disease—and potentially intervening. Organoids are used to model diseases like cystic fibrosis, cancer and Alzheimer's, to create customized cell therapies and, of course, to screen for drug toxicity. Unlike other model systems, organoids can mimic the complexity of a full human biological system, captured in the mesmerizing images that convey the wonder of that complexity.  

Compared with conventional in vivo methods, liver organoids can predict DILI with extraordinary accuracy—in some cases, nearly 89%.  But organoids have yet to take off as a widespread preclinical research tool. Creating the culture conditions to guide stem cells through all the correct developmental stages of becoming a usable organoid requires significant expertise that’s often only found in specialized labs. Additionally, most organoid cultures are still grown manually, which demands substantial labor and time. Artificial intelligence is playing a key role in expanding the insights organoids can reveal, but even AI can’t perform without a high volume of quality data to feed the models, meaning data generation and the protocols to guide it remain a bottleneck.  

From hand-mixed to standardized

“Much of our work has been focused on making the process of culturing organoids consistent, reliable and simple, all at a lower cost that makes scaling it up possible,” says Shantanu Dhamija, VP, Strategy & Innovation at Molecular Devices. 

The company’s system automates the cell culture process, eliminating much of the manual labor and boosting reliability and reproducibility. Other services, like custom organoid line expansion, take customer-supplied lines and scale them up to support next-generation drug discovery.  

“You can imagine our technology like a highly regulated oven, where scientists can essentially mix up their own cake recipes and get extremely reliable results based on what they put in,” says Dhamija. “Taking the analogy further, the next step in our work is to not just build the oven but provide cake mixes for the most important recipes as well.”  

The launch of the Danaher Beacon for Preclinical Drug Safety is such a step. One reality of the technical hurdles in culturing liver organoids is that they must often be sourced from a very small number of samples that represent a highly limited patient population. The Beacon will work to address this challenge, creating protocols and resources for stem cell-derived liver organoid systems that are biologically relevant, scalable, and reflective of the diversity of real patient populations, all with the goal of making it easier for researchers to improve drug safety screening.  

“Ultimately, our vision is to build on our ‘biological oven’ with a kind of cake mix approach that offers a suite of varied, diverse, and highly tested stem cell-derived liver organoids that make it easy for scientists to put these powerful model systems to work for patients,” says Dhamija.  

Pictured below: HepG2 cells tested and imaged to observe the impact of various drugs on cell viability.

HepG2 cells
From left to right: control (untreated), haloperidol (a first-generation typical antipsychotic), and rotenone (a natural compound used as an insectici

From left to right: control (untreated), haloperidol (a first-generation typical antipsychotic), and rotenone (a natural compound used as an insecticide and herbicide).


The future of safer drugs

“If the first 100 years of organoid technology were about modeling the complexity of an organ, its future will be about faithfully modeling the diversity of patients those mini organs need to represent,” says Chandra Ramanathan, VP and Head of External Innovation, Life Sciences Innovation Group, Danaher.

“We’re now looking beyond modeling a disease in a dish, and toward a population in a dish.”  

This development is especially pressing given increasing recognition of the need for diversity in clinical trials. Notably, while Black populations suffer disproportionately from DILI with higher rates of morbidity and mortality, suggesting a possible genetic predisposition, they are also significantly underrepresented in clinical trials, accounting for just 8% of clinical trial participants. 

More diverse and scalable liver organoids have the potential to become the next great tool in introducing more diversity earlier in drug development: a crucial step in accelerating discovery of new therapies, ruling out unsafe candidates earlier, and aligning on those that will make it through trials to market, saving time, money and lives all at the same time.  

“Organoids already mimic human organs better than any other system we have,” says Dhamija. “To us, and on behalf of patients waiting for safe and effective drugs everywhere, it’s clearly worth the investment to make this powerful tool as useful—and usable—as it can possibly be.”