3Rs Stimulus Fund: Computer model simulates concentrations in cells

3 years ago

The Utrecht 3Rs Stimulus Fund makes it possible to conduct small-scale 3Rs studies that ordinarily do not easily qualify for external financing.

One example is the research using computer models to estimate concentrations in human tissues following the administration of medicines. These models can considerably reduce – and perhaps ultimately replace – the use of laboratory animals. We talked about it with Anne Zwartsen, a researcher at the Institute for Risk Assessment Sciences (IRAS), in the Veterinary Medicine Faculty of Utrecht University and a recipient of a grant from the fund.

What did you use the grant for?

I built a computer simulation model in order to look at where the drug called Baclofen ends up in the body. Before that, I tested the effects of chemicals on the brain using in vitro tests based on brain tissue from rats. Colleagues were working on building computer models, so that in the long run we won’t need to test on animals. For me, that’s the future: computer simulations that predict in what concentrations medicines or other chemical substances end up in the body, and linking this information to the effectiveness or toxicity data of these substances.

You’re actually building a virtual person, with organs inside. You program how the blood circulates, and you build routes for administering the medication: orally, intravenously or injected in the cerebrospinal (spinal-cord) fluid. Then you determine to which tissues these medicines go, and in what concentrations, and how they leave the body. Afterwards, using in vitro tests, you determine if the chemical has a particular positive or negative effect on those organs.

How do you do that?

To test for effects on the brain, we normally take cells from the brains of rat pups. We grow them on special plates that have electrodes underneath them to measure the activity of the cells and the communication between the cells. Then we add the substance in various concentrations to see if this activity changes due to this addition.

Wat kind of medication is Baclofen?

It’s mostly used to reduce muscle spasms. I wanted to see how the medication distributes to nerve cells in the spinal cord, and in what concentration, given that that is where it causes its effect. I wanted to know through which administration route the highest concentrations are reached in the spinal cord. I also wanted to study how this concentration is related to the concentration in the blood. You don’t want a lot of this substance to end up in the wrong places, since it can cause side effects. With this information you can determine the best route for administration and the optimal dosage.

How has your research contributed to this development?

My colleagues and I were the first to build an intrathecal model (for administration through the spinal cord, ed.) for a pharmaceutical substance that acts on the nerve cells. Intrathecal administration is the best for this medication. The substance doesn’t have to pass through the blood-brain barrier, so you can get high concentrations in the nerve cells with a relatively low dosage. You have more side effects with oral and intravenous administration, since you need a higher dose to get enough of it to the destination. We already knew this from clinical studies and animal research, but it’s never been shown using a computer model before.

We were able to make the computer simulation more complex, and thus more realistic, by using a whole lot of data from previous research. What’s also great is that we can vary the computer model resemble specific patient subgroups. First, we built it for adults, and then for children. You can adjust it for body weight and for special conditions, like poor kidney function for example. You can do this for an individual patient as well as for a whole population.

What is the significance of your research for society?

It’s difficult to determine the concentration of medicines in the brain. You need to put a drain in the spinal cord to remove fluid. This is an invasive surgery, which is why this is often done with animals. However, we want a society with as little animal testing as possible, and that goes for this area as well, since it entails some obvious ethical dilemmas. In addition, the human physiology is different from animal physiology. Our computer model can help with this and built further on already existing data.

Are you planning follow-up research?

This model can be expanded to be used for other medications and chemicals. A colleague of mine is going to use this model to make a generic model for larger groups of substances. I’m actually going to start another job soon. I’ll be a toxicologist for the chemical water quality & health group at the water research institute KWR. KWR was recently a lot in the media because they found a way to identify the presence of the covid-19 virus in an area by testing its sewer water.

What role did the 3Rs Stimulus Fund play in these results?

I wouldn’t have been able to do this without the Fund. Everything was paid from it, including my salary and the experiments. It gives a beginning researcher the opportunity to learn something new, and it can be a stepping stone to a larger grant.

What is it about toxicology that intrigues you?

It’s an underappreciated area. Toxicological research enables you to prevent problems that would otherwise have to be solved after the fact. This does mean that you often come with a negative message, and the public doesn’t always like that. Things come out of it that you might not want to know, but that you ought to want to know.