Exploring the newest alternative to animal testing: brain organoids

It was a big win. A new US law was passed 打開新的分頁／視窗 in the final days of 2022 that made animal testing no longer a requirement for drugs to receive US Food and Drug Administration (FDA) approval — mirroring similar developments in Europe 打開新的分頁／視窗. For Dr Thomas Hartung 打開新的分頁／視窗, these shifts represent the fulfilment of a long-held dream. 

“With around 50% of Americans and 60% of Europeans now opposed to animal testing, it’s actually just a logical response from policymakers,” he notes. “It also reflects how the discussions are now less about ethics and more about technology. Today, there are simply much better testing options available, which are faster, cheaper and more human-relevant. These disruptive technologies have really given the whole field a lot of acceleration.” 

Steering the revolution away from animal testing

As the Director of the Center for Alternatives to Animal Testing (CAAT) at Johns Hopkins University 打開新的分頁／視窗, Dr Hartung was an obvious choice to appear in Elsevier’s Successful Alternatives To Animal Testing 打開新的分頁／視窗 webinar series in 2022.

Finding a niche on which to expand

“I never dealt well with animal testing,” says Dr Hartung when asked about the roots of his passion. “I love animals. But that said, I definitely chose the wrong profession. If you work in pharmacology, toxicology or infectious diseases, it’s very difficult to avoid animal testing. So long ago and faraway, I did work with mice and rats. And in the evening afterwards, I would need a very large glass of whisky.”

Happily, he found another path while doing his PhD: “I was doing what I considered very mechanistic research working on cell models of certain diseases. But then the head of the animal research facility — who today remains a very close friend — told me that I was actually doing alternatives to animal testing. This opened a door for me. I started to attend all these new conferences taking place and very quickly became part of this movement.

“In the beginning, many people warned me I might endanger my wonderful career by going so niche. But fortunately, life has proven them wrong,” he chuckles. 

From stem cells to brain cells to organoid intelligence

In his own work, Dr Hartung felt technology accelerate while doing brain research. “We were very driven by this epidemic in autism 打開新的分頁／視窗. Back in the 1970s, one in 10,000 were diagnosed with autism. Today, it’s one in 36 and rising 打開新的分頁／視窗 — though this is likely also related to wider testing. But the animal experiments around autism are useless. They don't pick anything up and they cost $1.4 million per chemical. So, we’ve been working since 2005 to replace this with an in vitro battery of tests — ideally in conditions that mimic a living brain.” 

“But if I asked you for some of your brain cells to experiment with, you’d likely decline,” he jokes. “That’s why producing cultures of human brain cells was a longstanding aim in the field. So, when human stem cells became ethically available in 2006, this was a big leap forward.”

“But first we had to figure out how to develop brain organoids — 3D cultures of human brain cells — from these stem cells. And in 2016, we became only the fourth group to start producing these — and the first to mass produce standardized ones. This opened up the possibility for toxicity testing and pharmacological testing on such organoids.”

This development was also a boon to pure neuroscience offering the opportunity to reproduce cognitive functions, such as learning and sensory processing, in a lab-grown human-brain model. “And this is what we call organoid intelligence: OI,” says Dr Hartung. 

From organs to systems

In turn, these brain models could be applied to creating larger microphysiological systems (MPS). “As a result, in vitro tools such as microfluidic organs-on-a-chip have rapidly evolved to recreate human physiology as well as key biological processes and disease states,” says Dr Hartung.

Other factors such as patient backgrounds and genetic components can now also be looped in to get an ever-larger — and more human-relevant — picture. “It’s about creating models to help us really understand how we think, learn and memorize, and then to use this for identifying substances which could fuel or treat conditions like autism or Alzheimer’s. We have seen so many drugs fail in Alzheimer research, so we really hope this is a new avenue for discovery.” 

“At one point, we might end up with something sentient”

Yes, these innovations have also spurred controversy. “When I first presented in 2016 on the brain organoids we are producing, some people were shocked and thought somehow these would spontaneously become physiologically active — that these cells would short-circuit and start communicating or something,” says Dr Hartung. 

“But these cells have nothing to think about: there’s no input or output. And this actually gave me the idea: let’s give them input and output. And that’s what we’ve been busy with for the last three years.” Basically, the hope is to create biocomputers where the lab-grown brain organoids serve as biological hardware — a dizzying proposition since when it comes to size, the human brain’s computational power remains unparalleled. 

But challenges remain. First, the cultures need to be scaled from their current 50,000 neurons to 10 million. Secondly, a brain-computer interface — an EEG cap for organoids 打開新的分頁／視窗 — must be further developed so signals can be more effectively sent and received. Meanwhile, Dr Hartung remains confident. Already, some fellow researchers have taught a “DishBrain 打開新的分頁／視窗” to play Pong.

The ultimate technological goal is to integrate organoid intelligence with artificial intelligence and “watch the magic.”

But naturally, this does come with ethical questions. “At some point, we might produce something which is sentient or conscious, and that’s why we have ethicists strongly involved from the beginning. And things are moving fast,” Dr Hartung says. “Over the last 12 years, AI has doubled in capacity every three months.

“So even though OI is still in its infancy, I think we can still expect a lot in the next year.”

Bringing change management to animal testing alternatives

Naturally, there’s also still much work to be done around alternatives to animal testing. “But my views around this have changed in recent years,” Dr Hartung says. “I think it’s much less about developing alternative methods; we already have sophisticated cell models. AI alone is already largely outperforming many types of animal experiments. Now it’s more about change management. It’s about evidence integration — since it’s no longer about that one tool but the many we have at our disposal. So, this is really much more of a managerial exercise.”

Hence, innovators such as Dr Hartung can maintain their focus on OI.