Animal testing is crucial for measuring the efficacy and safety of new treatments. It’s also a step that everyone would like to avoid as much as possible for a range of economic, regulatory, and ethical reasons. But what are the alternatives, and can they really reduce the use of animals in drug development?
Before a company lets a treatment anywhere near humans, the company needs evidence that it’s likely to be both safe and effective. This has historically been done by testing the drug on living animals (in vivo), and more recently in human cells or tissue in a dish (in vitro).
In general terms, in vitro testing is cheaper and quicker than in vivo, but testing in animals, most commonly mice, is thought to give a better picture of how a treatment behaves in a living organism. While the predictive value of animal models does vary depending on the diseases and treatments in question, a company must always show that its treatment is safe and effective in animal models to get past regulatory hurdles.
With advances in biotechnology, we’re now able to better mimic human organs and physiology. If these technologies prove better than animal testing at predicting the effects of a drug on the human body, they could eventually replace some of the animal testing currently required in drug development. This could make it cheaper and quicker to get new disease treatments into the clinic and eventually to patients.
It’s unlikely that animal disease models can ever be replaced fully, but some researchers and biotechnology companies are changing the face of drug development, and reducing our reliance on animal models.
Without further ado, let’s examine some of the most interesting technology that could help reduce the number of animals that give their lives for the sake of medicine.
3D printing has revolutionized the tech world for its potential to produce complex machine parts from a digital file. Now imagine this but for making living tissues — you have tissue bioprinting in a nutshell. While regular printing and 3D printing have their own different inks to use, bioprinting uses bioinks, which are usually gels that can carry cells.
Replicating the 3D structure of a human tissue can give a lot more information about a drug’s effect than cell cultures. For example, the French bioprinting company Poietis is working with the pharma Servier to develop a bioprinted liver model that can test the toxicity of drugs in a more complex environment than in cell cultures.
“Few companies in the world use bioprinted tissues in the drug discovery process,” Kevin Fournier, Sales Manager at Poietis told me. “But every year more and more companies choose to use bioprinting technology for their applications. Some experts are betting on a huge explosion of this technology over the coming years.”
One particular area of interest for the bioprinting field is cosmetics. Since the EU banned animal testing in cosmetics research back in 2013, the French giant L’Oreal has been working with the US biotech Organovo to produce bioprinted human skin for testing its products.
Tissue bioprinting is still at a very early stage. “At the moment, there are no studies that compare animal models to bioprinted models,” Fournier said to me. “We bet that, over the next ten years, bioprinting technologies will offer [animal model] alternatives that are closer to native human tissues and also, that are more ethical, responsible and more affordable than animal models. We all have a lot to win by changing our model habits.”
Aside from pure drug development, tissue bioprinting could actually go a step further than animal models by enabling more personalized approaches in medicine. One example of this is a collaboration between Swedish company Cellink and France-based biotech CTIBiotech to print tumor tissue derived from patients. This technique can model a patient’s 3D tumor, and allows companies to test specific drugs on the models to figure out which help the patients best.
Cell cultures are tried and tested methods for screening drugs, but how cells behave in a dish is not necessarily how they behave in the body. One alternative could be organoids, or miniature organs. Organoids are grown using 3D clumps of stem cells, and, with the right cocktail of nutrients and treatments, become a little organ of your choice.
Like with bioprinting, organoid research is still in its early stages, but there are several companies developing the tech. Sun Bioscience in Switzerland is using organoids to model the intestine in the genetic lung disease cystic fibrosis. In the Netherlands, OcellO offers organoids modeling cancer, such as colorectal cancer.
“Colorectal cancer is the most advanced organoid field scientifically,” Leo Price, the CEO of OcellO, told me. “Development needs to occur in immuno-oncology, immunology, neurodegeneration, diabetes, obesity and fibrosis — all areas where the tissue architecture is going to be critical. Simple cultures of cells on plastic aren’t going to cut it.”
As well as companies, there is an active academic community developing organoids, with at least two groups modeling the placenta, and even efforts to develop brain organoids for modeling neurological diseases.
One common drawback of organoids stopping them from going more mainstream is that it’s hard to manufacture them reliably for the commercial scale. Another is that it’s currently tricky to model a diverse set of cells — what you’d have in patients — instead of a simple blob of the same cell type. There’s work being done to overcome this, but there’s still a long way to go.
Like bioprinting, organoids could have big uses in advanced in vitro testing in early drug development, and even in personalized medicine.
“Organoids are reducing animal experiments,” Price told me, adding that the first stages of animal testing could be done instead in organoids, with only a final validation needed in the animal.
Organ-on-a-chip technology consists of growing cells inside of tiny chips to mimic the structure and behavior of organs and organ systems. Because of the small size of the chips, researchers can test drugs more quickly and cheaply than in animal models. Unlike animal models, organs-on-chips can also use human-derived tissue, which helps to create a representative model.
“The organ-on-a-chip field is only maybe six or seven years old,” Jos Joore, CEO of the Dutch organ-on-a-chip company Mimetas, told me. “It has a huge promise on its shoulders, and is actually coming up with good predictive disease models.”
The cells and tissue grown on chips can vary widely depending on the organ that you are modeling, with liver, kidney, heart and even brain cells available.
One standout characteristic with organs-on-chips is that there’s theoretically no limit on the number of organs you can mix on a chip, which could be useful for studying a drug’s effect on organ interactions. In fact, the UK company CN Bio is developing a system incorporating ten organs on a single chip.
Could this organ interaction system one day replace animals? No, opined Joore. In fact, mixing too many organ systems may be missing the main strength of the technology, which is making simple disease models in human tissues easy and quick.
“When you start connecting these tissues, the complexity increases exponentially,” he continued. “I don’t even want to think about connecting ten tissues because at the end of the road, you’re making, I would say, a Frankenstein’s monster, which you can hardly control anymore.”
Notwithstanding, the organ-on-a-chip field is advancing fast, with more and more complex models appearing, such as liver-on-a-chips used to develop treatments for hepatitis B, and Mimetas’ recent publication testing kidney tubules on a chip.
The future of animal testing in research
Bioprinting, organoids and organs-on-chips are all early stage technologies with the potential for making in vitro research more representative of humans. While they are big improvements over traditional cell cultures in the drug development process, they are still limited in regards to predicting the behavior of a drug in a person. This means that animal models are still likely to be a common drug development tool in the future, as a way to validate the in vitro models.
One big issue with animal research is that animal testing doesn’t represent human patients perfectly. This is particularly the case in neurodegenerative diseases such as Alzheimer’s disease, where many drugs have failed in the clinic after showing promise at the preclinical stage.
“Animal models, on a general level, are not very predictive,” Joore from Mimetas remarked. “If animal models worked perfectly, you wouldn’t have 90% attrition when you start doing a clinical trial.”
Chris Magee, Head of Media and Public Affairs at the UK organization Understanding Animal Research, told me that animal models are actually great at safety predictions, but less predictive around drug efficacy, often because experiments have been oversold or badly designed in the past. This has improved a lot over the years.
“Scientists know that mice aren’t tiny humans,” Magee commented. “In recent years there’s also been less of a tendency to over-promise on the basis of animal studies.”
There’s also another emerging technology that could reduce the use of animal models: simulating the drug on a computer, or in silico. Consensus so far is that, although this field is at a very early stage, it does contribute to the analysis of experimental data, and therefore to improving the science of drug development.
So, can biotechnology reduce animal testing in medicine? For the near future, animal models in drug development are here to stay. But, they should decrease a lot, and this fall in usage will be due both to the rise of new techniques in biotechnology, and to better experimental design.
As the use of animal models decreases, scientists will be improving their experimental design and data analysis, getting the most out of each experiment. By advancing these techniques, drug development gets cheaper, faster and more ethical; so everyone’s a winner.
Images from Shutterstock, NIH Flickr, Cellesce