Stevens Rehen is a neuroscientist at D’Or Institute, licensed professor at the Institute of Biology at the Federal University of Rio de Janeiro (UFRJ) and visiting scientist at Promega Corporation and the Usona Institute. Throughout his career, Rehen has published over 100 scientific articles, served as president of the Brazilian Society of Neuroscience and Behavior, and pioneered the cultivation of human embryonic and induced pluripotent stem cells (iPS), and brain organoids in Brazil.

In this interview, the researcher explains what induced pluripotent stem cells, or reprogrammed cells, are and how they create organoids. He also shows the different research he has developed using brain organoids: studies ranging from the search for drugs for Alzheimer’s to the effects of psychedelic substances on the brain, passing through research on viral diseases such as zika and covid-19. Stevens Rehen also addresses the challenges facing Brazilian science in relation to organoid research and envisions possibilities for the future.

Pioneer Science: You have been working on projects involving induced pluripotent stem cells for some time now. What are these cells and what is the interest in studying them?

Stevens Rehen: In 2007, based on the work of researcher Shinya Yamanaka, it became possible to reprogram human cells. In a way, it was as if researchers managed to gain access to information that was hidden in adult cells. For example, our brain cells have the ability to form a heart instead, but of course they don’t – imagine how crazy it would be if there were specialized cells popping up in random places in our bodies, places where they don’t belong? Based on this technology, developed in Japan, it was possible to create cells with embryonic characteristics from skin or urine cells.

I have been studying brain tissue for almost 30 years, but it was in 2008 that I began to take advantage of reprogrammed cells and the possibilities they open. We can reprogram cells obtained from patients with Alzheimer’s, epilepsy, or any other disease.

We are able to study characteristics of a patient’s brain with cells extracted from urine or through a skin biopsy. That’s where the beauty of this experimental model lies.

What is the status and what are the prospects for using reprogrammed cells to develop new treatments or to understand disease models?

It is booming; it is an area of great scientific interest worldwide, not only in the academic area, but also within biotech companies, as it is a promising experimental model for research and drug screening. In the case of degenerative diseases, for example, it is possible to identify, in brain organoids, cellular phenotypes that are equivalent to those that appear in the patient.

What are organoids, specifically brain organoids?

The cells in our body are organized and communicate in complex structures, such as tissues and organs, not simply in a single, two-dimensional layer, but in three-dimensional structures. Today, researchers can give instructions for the reprogrammed cells to grow in the laboratory according to the base tissues of the human being. In the case of brain tissue, these cells manage to organize themselves into structures that resemble the human brain but can only reach up to 5 mm in size – they do not grow further, because they lack vascularization to make the tissue grow. These organoids, which can reach around 5-10 million cells, are the brain organoids.

Through them, we can observe in the laboratory some characteristics of the metabolism of the living brain.

What can be investigated from organoids?

With them, we have a living, human experimental model in the laboratory. A concrete example is Alzheimer’s disease. We can observe, in the organoids, characteristics of the brain with the disease, an increase in the phosphorylated form of the tau protein and the formation of beta-amyloid plaques. From these observations, it is possible to test drugs or conditions to mitigate what we observe in vitro and which are equivalent to what is observed in vivo as well. We can also study Dravet Syndrome, which is a severe form of childhood epilepsy caused by a specific mutation.

Here at D’Or Institute, we had access to children’s urine, reprogrammed the cells and now, we are studying the electrical activity of the created brain tissue, which reproduces the epileptic seizures that we observe in patients. We also work with viral infections. Our group was the first to show, through organoids, how the Zika virus infection occurs. We did something similar with SARS-CoV 2.

Can you tell us more about the group of researchers who work with you in the IDOR laboratory?

In 2013 I joined the IDOR group. We have around 15 people working in the laboratory, including staff and students. We have projects financed both in Brazil and abroad.

What were you able to learn about growing brain organoids and the uses of organoids in neuroscience?

Learning is constant. We always need to seek the state of the art of science, and keep up with other research groups in other countries. We have generated important contributions during the Zika virus epidemic. We have several works on the subject: we identified the human brain cells affected by the disease; the consequences of infection for the functioning of brain tissue. We also had significant results regarding the biology of schizophrenia and the role of brain cells from patients with this mental disorder in the formation of blood vessels.

We also study psychedelics. Using brain organoids, we identified the effect of an ayahuasca-derived compound that interferes with the transport of a protein associated with Alzheimer’s disease. We have another scientific article in which we show that LSD has an effect on neuroplasticity. We carried out this study on organoids and then complemented the tests on humans and animals. We also work with 5-MeO-DMT, which is a psychedelic produced by a frog. We observed that this compound has an effect on neuroinflammation.

Regarding the studies with psychedelics: when did this work begin? And why work with psychedelics from organoids?

The interest in psychedelics came from the privilege I had to follow the work of my younger brother, Lucas Kastrup, who is an anthropologist and musician. He studied the construction process of songs associated with religions that have ayahuasca as a sacrament. They are traditional religions in Brazil that are based on the consumption of ayahuasca. In addition to following the work done by my brother, I also observed the work of colleagues such as Sidarta Ribeiro, Dráulio Araújo and Luís Fernando Tófoli, who are scientists in the field of neurosciences and psychiatry and who have been conducting interesting studies on psychedelics for many years. In 2013, I began to wonder how our experimental model of organoids could contribute to understanding the effect of psychedelics on the brain.

How is the organoid research scenario in Brazil and worldwide?

There are several research institutions dedicated to studying organoids and identifying human disease phenotypes. That development has been impressive, including in Brazil. But here we have other challenges that are linked to a lack of support for science at the universities in recent years.

In ten years, how do you see the state of research regarding brain organoids?

I believe that, within a decade, research on brain organoids will be significantly advanced.

A recent decision by the United States’ FDA already signals a tendency to encourage alternative research models that do not involve the use of animals.

As a result, we can expect an increasing sophistication of experimental models, where organoids will be combined with emerging technologies such as microfluidics systems, providing deeper and more accurate insights into the functioning of the human body.

See also the infographic “Application of brain organoids in psychedelic research”. In it, we show how brain organoids can be applied to answer different scientific questions.