3Rs Stimulus Fund: Micro-environment of the bone

3 years ago

Silvia Mihaila is an Assistant Professor at the Division of Pharmacology, Department of Pharmaceutical Sciences, Utrecht University. She received a grant from the 3Rs Stimulus Fund for her research on developing in an vitro model of uremic bone disease.

What is your research about?

I’m trying to recreate the micro-environment of the bone. I'm working in a group mainly focused on human-specific diseases, so my research is focused on replicating human-specific diseases. Specifically, I'm looking for the connection between kidney disease and other remote organs.

When kidneys fail, the entire body is affected. The kidneys are where vitamin D is activated. That is important for keeping bones healthy. When your kidneys fail, vitamin D is not activated. Vitamin D is needed to absorb calcium and a lack of calcium causes bones to become fragile. Kidneys also clean the waste caused by metabolic activity. Another effect of kidney disease is that the kidneys are unable to cleanse the blood. Toxins remain in the blood and accumulate, so this stains the blood. This blood circulates the whole body. This is how other organs are affected as well. A kind of domino effect occurs in the body where many organs in the body start to fail or don't function properly. One of them is the bone. The quality of life is very poor for kidney patients. They have to take a lot of medication to treat all the secondary issues.

Bones are seriously affected by kidney disease. In my research, I'm trying to recreate the micro-environment of the bone in the conditions where the kidneys are damaged. The bone is a very dynamic organ, it is constantly being broken down and rebuilt. For example, if you have a fracture, the crack is immediately filled with new bone. But if a kidney patient has a fracture, the environment is too toxic for the cells to rebuild the bone and the quality of the new bone will be poor. These patients suffer from a lot of fractures.

In the bone, some cells build up the bone and some cells break down the bone. There has to be a balance between these cells. In the case of a kidney patient, more cells are breaking down than building up. I culture these cells in a lab under healthy conditions and uremic conditions. This is fully done in vitro. I then try to see what can be done to stimulate bone production.

What has the grant made possible for you?

The grant was a vote of trust that allowed me to focus more on bones instead of just the kidneys. There was an indication in the literature that there could be a connection between the kidney and the bones, but existing literature was sometimes contradictory. There were also not that many in vitro models available because most researchers were focused on creating healthy bone instead of diseased bone. I wanted to pursue this niche and the grant allowed me to explore this idea further. I applied for the grant and the committee believed in it. It opened up a lot of possibilities to conduct research in this field. The stimulus fund is exactly what it says, it is a stimulus. Sometimes you just need a little push to expand the possibilities for your research.

Why is your research important?

In the first week of my new job, I took a tour of the nephrology unit. I was shocked, I had never before seen patients suffer so much. Patients who go on dialysis need to stay at the hospital for hours at a time, multiple times a week. Otherwise, they will die. These patients have a strong will to live but it comes at a great price. They are dependent on a hospital, so there is a limit to what they can do in life.

As a researcher, I felt the responsibility to conduct research that helps people, not just conduct research out of curiosity. With my background in bone regeneration, I found out that kidney patients often experience bone issues. If I can do something that will improve the quality of life for these patients, I want to do that. That is why I think my research is important.

Most of the research in this field is done using clinical observations. The problem is that patients are unique and kidney disease is complex, so many studies come up with conflicting data. To get more accurate data, sometimes animals are used. In this case, you need to make an animal as sick as a kidney patient. But it takes months for an animal to become that sick. In the meantime, the animals are suffering. Sometimes animals are more resilient than humans, so they end up surviving without dialysis. These studies are ethically questionable not matched to biological aspects of humans. In my research, I try to avoid using animals, so I think in vitro research is very important. Instead of using animals as a starting point, I think we should use in vitro as a starting point.

What are the challenges you face?

I am looking at human bone disease, so I want to work with human cells. But getting cells from real bone takes a lot of time and is not always efficient. I use stem cells and building new bone from scratch takes one to two months, just like the time it takes for a fracture to heal. Another challenge is that I try to mimic as much as possible, but sometimes I cannot mimic everything. One model cannot answer multiple complex questions, so I need to keep the model simple, but detailed enough to be accurate. A limitation of in vitro research is that you cannot see how organs respond to each other. Right now, it mostly comes down to technical limitations, but I believe that in Utrecht we have the know-how to address these limitations. Researchers realise what the limitations are and look for ways to overcome them.

What do you hope to achieve?

With my research, I hope to improve the quality of bones using an in vitro model. The more we can replicate the conditions in humans, the better we can understand it. This will help us fight it and improve the health of patients. Once we have established and validated the model, I want to develop some sort of screening platform where you can put in your research question and medication to see what the potential effect will be.

What is your hope for the future?

There is already a lot of awareness about in vitro models, but I hope that we continue to explore the possibilities these models have to offer. Not just within universities but in other industries as well. For example by inviting pharma companies and regulators to be part of the conversation. I also think the new generation should become aware of the value of in vitro models. I am involved in some courses that address this issue, so in Utrecht we have already made the first step.

Working with in vitro models should become part of our way of thinking. When you start a new experiment, in vitro should be plan A. I would also like the different research groups in Utrecht to support the dialogue between these groups more. I ended up in a kidney group when I was working with bones before. If we are more visible to each other, we can make better connections and collaborate more. Ultimately, this will help us make a difference for patients and improve animal welfare.