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Using human organoid technology to treat viral infections in children

Dasja Pajkrt is Professor of Viral Paediatric Infectious Diseases at Amsterdam UMC/AMC and Co-head of OrganoVIR Labs – a laboratory with researchers who are leading innovation in the field of organoids for virology. Dasja’s team focuses on viral infections (in children), and uses human-derived organoids to study these viral infections. We talk to her about her research so far, how it contributes to animal-free innovations, and what’s next in the field of organoid technologies.

What’s the focus of your current research specifically?
My team is looking specifically at three groups of viruses that can severely affect children: picornaviruses, which are responsible for illnesses like meningo-encephalitis and sepsis; cytomegalovirus (CMV), which isn’t an issue for young children and adults but can cause severe disabilities in children born with CMV; and HIV, which is well known. All three virus groups affect adults too, of course, but they cause different problems in children. For example, adults with HIV can be treated nowadays. But children with HIV are often also neurologically impaired, even under optimal treatment. The mechanism of the disease works entirely differently in children compared with adults.

What’s unique to our research is that we’re using human-derived organoids to study these infectious diseases. We take stem cells, feed them with various growth media, and give them the time they need to develop into organoids. Depending on the stem cells you start with and the type of growth media, you can grow different organoids. We started simple, but we’re now making more complex structures involving multi-organ systems.

In a nutshell, we identify a question in the clinic (a child infected with a virus) and we look for answers in the lab (using organoid technologies). We employ these organoids as a tool to study and treat viral diseases.

Why is this bridge so important?
The bridge from the patient to the lab and back again is crucial to our research. Effectively, I translate human paediatric diseases from the clinic into something that we can study in the lab using human-derived organoids. We can then use this research directly to benefit patients.

To take a recent example: we got a request from the intensive care unit at Amsterdam UMC because they had admitted a mother with Covid-19 who had recently given birth. They wanted to find out whether it was safe for the mother to breastfeed her infant or whether it was likely to infect the child with Covid-19. Using a gut organoid and testing it with breast milk, we discovered that not only was the mother unlikely to infect her child, but that breastfeeding the child would actually offer protection against contracting Covid-19. That was a fascinating and very topical use of organoid research methods!

Why use organoids instead of animal-based research methods?
In the example I just mentioned, testing on animals would have been useless. It would simply not have told us the information we needed to know. And the same is true for many viral diseases. In children especially, it’s much more logical to use human-derived organoids than small animals like rats. To cite another example: the aging process of the human brain when in early development very closely resembles the aging of a brain organoid. The three virus groups that we are studying specifically impact brain development in children. So using stem cell-derived brain organoids is a far more effective tool to study these diseases than using animals.

Much of the research we’re doing could not have been carried out on animals in the first place, because data from animal trials often don’t translate well into humans. So it’s not even about replacing animal-based research – it’s about coming up with entirely new research methods that could never have been performed on animals.

What does that mean for animal trials then?
It means that we’re in a much better position to test new anti-viral drugs. Using our organoid models, we can already see whether they work. If the test is negative, then there’s no use testing on small animals – which saves a lot of time and money than if we had to test on animals initially. If the test is positive, then the treatment may still move into animal trials.

At the moment, it all depends on the funding. If the legislation requires animal studies, then we will still trial the treatment on animals. And currently, most regulators do still rely on this. If we reach a point where regulators are willing to rely on human organoid studies, then we can eliminate animal testing entirely. But as with all models, this takes time. The technology is only around 10 years old, so it’ll be some years before we’ve all learned to rely on these results.

How about human trials?
The best animal-free research is human studies. Clinical trials are essential. My PhD research involved injecting a person with a part of bacteria in order to test a specific drug to treat their reaction to that substance. But of course in many cases this isn’t very feasible or ethical: you can’t simply inject a person with HIV! In these cases, human-derived organoids are the next best thing.

What’s next for organoid research?
We’ve already come a long way: organoid technologies were initially used in toxicology. For instance, organoids were created from patients with a specific disease, such as cancer, to find out whether a particular treatment would be applicable to them. If the cancer was responsive in the lab, it made sense to give the treatment to the patient. But using organoids in viral research is new – and there’s still a long way to go.

We’re collaborating with lots of partners – including a large consortia of academics from the EU, private-sector companies with an interest in stem-cell technology, and public-sector bodies like the National Institute for Public Health and Environment (RIVM) and the Dutch Society for the Replacement of Animal Testing (DSRAT). But we also work with business schools, to teach our researchers business and managerial skills in addition to the scientific component, as well as ethics organisations that are concerned with the legislation behind human-derived organoid technologies. We need to collaborate more intensively with the public and private sectors to really get our models up and running when it comes to studying infectious diseases.

We already have an organoid lab at Amsterdam UMC, but we’d like to build a bigger and more professional facility so that other parties can test anti-viral treatments at our centre. This would help collaboration, too, so that we can work together better and faster.

We’ve been fortunate to have been given two substantial grants for our research by the EU, but our aim is to get additional funding subsidies from the Dutch government, the EU and via collaborations with private companies as well in the future.

Where can people go to find more information?
There are two great resources for information about human-derived organoid technologies:

  • OrganoVIR is a network of public and private experts and talented early-stage researchers, who team up to lead innovation in the field of organoids for virology. Their mission is to transform the virology landscape and establish human organoids as superior models for virus research.
  • GUTVIBRATIONS is a multidisciplinary international consortium of European partners from the fields of academia and industry that are developing a next-generation gut-brain axis organ-on-chip. This multi-organ system will simulate the human body and provides an animal-free solution for modelling human diseases and pre-clinical drug development.

Interview by Vicky Hampton, December 2021