How do medicines affect the placenta? Can early cooling protect the brain after cardiac arrest? Four researchers affiliated with the Department of Physiology and Pharmacology, FyFa, at Karolinska Institutet have received funding from the Swedish Research Council. The projects focus on medicines during pregnancy, cardiac arrest, the hormonal condition PCOS and fatty liver disease.
- For the four researchers, the funding now provides an opportunity to take the next step in their work, whether that means testing models of the human placenta, conducting a large European patient study or investigating the mechanisms behind disease, says Sophie Erhardt, professor and head of the Department of Physiology and Pharmacology.
We interviewed the four researchers about what the funding makes possible, which questions they want to answer and how the results could, in the long term, contribute to better treatments.
Cristiana Cruceanu: Placenta models for research on medicines
What does the grant mean for you and your research?
- We can now investigate how well models built from human cells mimic the placenta. This is a goal I have worked towards since I started the group at KI. In the long term, the models may reduce or replace animal testing in research on medicines during pregnancy, says Christiana Cruceanu.
What will you investigate, and what is new about the method?
- Almost no approved medicines have been tested specifically during pregnancy. In addition, the human placenta differs from the animal models used today, especially in early pregnancy.
We will grow small three-dimensional models of the human placenta, known as trophoblast organoids. For the first time, we will systematically investigate how well they mimic the placenta and its responses to medicines. We are starting with antidepressants, but hope that the method can later be used for other groups of medicines.
What can the models show?
- They contain the key cell types found in the early placenta. We can measure how much of a medicine passes through the model and see which cells are affected. We are also investigating whether responses differ depending on the biological sex of the foetus.
What do you hope the project will lead to?
- I hope that other researchers will be able to use the models and our working methods. We want to create an open digital map of how placental cells respond to a group of antidepressants called SSRIs. We will also share measurement data comparing the models with human placentas and animal models.
The models cannot replace studies in humans, but they can help researchers design better studies. In the long term, we hope the knowledge can contribute to more well-founded recommendations on medicine treatment during pregnancy.
Per Nordberg: Early cooling to protect the brain after cardiac arrest
In PRINCESS2, researchers at several European hospitals are investigating whether early cooling of the brain after cardiac arrest can improve survival without serious brain damage. The treatment begins before arrival at hospital.
What does the grant make possible?
- We can continue the study as planned, with around 30 study centres in eight European countries, says Per Nordberg.
How does the study differ from previous research?
- We are moving a treatment that is normally given in intensive care to the place where the cardiac arrest occurs. A specially developed, portable cooling method means we can start about three to four hours earlier than in previous hospital studies.
How could the results affect care?
- If the study shows positive results, they could influence guidelines for early cooling treatment.
What do you hope the study will mean for patients?
- That more people survive with the opportunity to return to the activities they took part in before the cardiac arrest and have a better life.
Elisabet Stener-Victorin: The interplay between tissues in PMOS
Polyendocrine metabolic ovarian syndrome (PMOS, formerly PCOS) is a hormonal condition that can affect menstruation, fertility, glucose regulation and metabolism. Elisabet Stener-Victorin is investigating how the endometrium and adipose tissue interact to better understand the mechanisms behind the condition.
What does the grant make possible?
- For the first time, we can study the endometrium, adipose tissue and immune cells in the blood from the same women, both before and after treatment. We are building on our previous mapping of endometrial cells in PMOS. Now we can track how they change during the menstrual cycle and link this to what happens in adipose tissue.
What do you want to find out about the interplay between the endometrium and adipose tissue?
- We want to understand how adipose tissue that is not functioning as it should, together with high levels of male sex hormones and insulin, affects the endometrium. This may help explain why an embryo has more difficulty implanting and why the risk of miscarriage is higher. We also grow small tissue models, known as mini-organs, from the patients' own tissues. With these, we can study how the tissues communicate and how they are affected by hormones and medicines.
Why is it not enough to study one tissue at a time?
- PMOS affects the whole body. Adipose tissue produces hormones and sends signals to other organs. Among other things, it can convert hormones into more active male sex hormones. If we only study the endometrium, we see the consequences but risk missing the causes. By tracking the signals between tissues, we can better understand what drives the disease.
What do we still know too little about?
- We know that hormones, metabolism and the immune system are involved, but not how they interact in different cell types. It is also unclear why the condition varies so much between women. We have recently described different subgroups of PMOS. The next step is to understand which biological mechanisms distinguish them.
How could the results improve care in the long term?
- Today, we mainly treat the symptoms, and the same treatment does not help everyone. We hope to find biological markers that show who will benefit from a particular treatment and identify what new medicines could target in the affected tissues. This could make care more personalised. The aim is to increase the chance of becoming pregnant and reduce the risk of miscarriage, type 2 diabetes, cardiovascular disease and endometrial cancer.
Shane Wright: Seeking new treatment approaches for fatty liver disease
What does the grant mean for you and your research?
- It means a great deal to me and my research group. It gives us the opportunity to use our knowledge of G-protein-coupled receptors, GPCRs, to develop new molecules that could eventually become medicines. It is an ambitious project, and support from the Swedish Research Council enables us to explore new ways to treat fatty liver disease.
What will you investigate?
- We want to understand how different GPCRs affect the cellular processes involved in fatty liver disease. These receptors help cells receive signals. Above all, we want to investigate what happens when we target treatment at several receptors at the same time, rather than one at a time. The aim is to identify promising combinations that can be used to develop new treatments.
Why are these particular receptors of interest in fatty liver disease?
- Many current medicines work through GPCRs. These receptors control several of the body's functions, including metabolism. That makes them interesting in fatty liver disease. The first medicines specifically approved for the more severe form of fatty liver disease, MASH, have recently become available. These are important advances, but treatment options are still limited and do not help everyone. We therefore need more medicines that work in different ways, and we believe GPCRs offer great potential.
What is new about your approach to tackling the disease?
- Most medicines are designed to affect a single target in the body. We instead want to develop molecules that affect carefully selected combinations of GPCRs. This could bring together several beneficial effects, improve treatment efficacy, or make treatment more targeted to certain cell types. Our knowledge of how the receptors work and how they are affected by medicines will help us choose which ones should be targeted together. We will then design molecules that can do this.
What do you hope the project will lead to?
- In the long term, we hope to develop new drug candidates that work in different ways from today's treatments. By affecting several receptors, we may achieve a better effect or target treatment more clearly to certain tissues or cell types. This could also reduce unwanted side effects. Since current treatments do not help everyone equally well, medicines that work in different ways could provide more treatment options. We are focusing on fatty liver disease, but the approaches could also be used for other diseases.
What makes you most hopeful about this method?
- That we can move from studying individual receptors to using our knowledge of them to develop new medicines. We already know that GPCRs are good drug targets, but we have only just begun to explore what is possible when several are affected at the same time. I believe there is great potential to develop medicines with properties that we cannot achieve by affecting a single receptor.
