From The Swiss Federal Institute of Technology in Zürich [ETH Zürich] [Eidgenössische Technische Hochschule Zürich] (CH): “Mapping human brain development”

From The Swiss Federal Institute of Technology in Zürich [ETH Zürich] [Eidgenössische Technische Hochschule Zürich] (CH)

Peter Rüegg

Researchers at ETH Zürich are growing human brain-​like tissue from stem cells and are then mapping the cell types that occur in different brain regions and the genes that regulate their development.

Brain organoid from human stem cells under the fluorescence microscope: the protein GLI3 is stained purple and marks neuronal precursor cells in forebrain regions of the organoid. Neurons are stained green. (Photograph: F. Sanchís Calleja, A. Jain, P. Wahle / ETH Zürich)

The human brain is probably the most complex organ in the entire living world and has long been an object of fascination for researchers. However, studying the brain, and especially the genes and molecular switches that regulate and direct its development, is no easy task.

To date, scientists have proceeded using animal models, primarily mice, but their findings cannot be transferred directly to humans. A mouse’s brain is structured differently and lacks the furrowed surface typical of the human brain. Cell cultures have thus far been of limited value in this field, as cells tend to spread over a large area when grown on a culture dish; this does not correspond to the natural three-dimensional structure of the brain.

Mapping molecular fingerprints

A group of researchers led by Barbara Treutlein, ETH Professor at the Department of Biosystems Science and Engineering in Basel, has now taken a new approach to studying the development of the human brain: they are growing and using organoids – millimetre-sized three-dimensional tissues that can be grown from what are known as pluripotent stem cells.

Provided these stem cells receive the right stimulus, researchers can program them to become any kind of cell present in the body, including neurons. When the stem cells are aggregated into a small ball of tissue and then exposed to the appropriate stimulus, they can even self-organize and form a three-dimensional brain organoid with a complex tissue architecture.

In a new study just published in Nature [below], Treutlein and her colleagues have now studied thousands of individual cells within a brain organoid at various points in time and in great detail. Their goal was to characterise the cells in molecular-genetic terms: in other words, the totality of all gene transcripts (transcriptome) as a measure of gene expression, but also the accessibility of the genome as a measure of regulatory activity. They have managed to represent this data as a kind of map showing the molecular fingerprint of each cell within the organoid.

However, this procedure generates immense data sets: each cell in the organoid has 20,000 genes, and each organoid in turn consists of many thousands of cells. “This results in a gigantic matrix, and the only way we can solve it is with the help of suitable programs and machine learning,” explains Jonas Fleck, a doctoral student in Treutlein’s group and one of the study’s co-lead authors. To analyse all this data and predict gene regulation mechanisms, the researchers developed their own program. “We can use it to generate an entire interaction network for each individual gene and predict what will happen in real cells when that gene fails,” Fleck says.

Identifying genetic switches

The aim of this study was to systematically identify those genetic switches that have a significant impact on the development of neurons in the different regions of brain organoids.

With the help of a CRISPR-Cas9 system, the ETH researchers selectively switched off one gene in each cell, altogether about two dozen genes simultaneously in the entire organoid. This enabled them to find out what role the respective genes played in the development of the brain organoid.

“This technique can be used to screen genes involved in disease. In addition, we can look at the effect these genes have on how different cells within the organoid develop,” explains Sophie Jansen, also a doctoral student in Treutlein’s group and the second co-lead author of the study.

Map of a brain organoid: The colours of the cells shown as circles indicate different cell types. Right: Regulatory network of transcription factor genes that controls the development of a brain organoid. (Graphics: Barbara Treutlein / ETH Zürich)

Checking pattern formation in the forebrain

To test their theory, the researchers chose the GLI3 gene as an example. This gene is the blueprint for the transcription factor of the same name, a protein that docks onto certain sites on DNA in order to regulate another gene. When GLI3 is switched off, the cellular machinery is prevented from reading this gene and transcribing it into an RNA molecule.

In mice, mutations in the GLI3 gene can lead to malformations in the central nervous system. Its role in human neuronal development was previously unexplored, but it is known that mutations in the gene lead to diseases such as Greig cephalopolysyndactyly and Pallister Hall Syndromes.

Silencing this GLI3 gene enabled the researchers both to verify their theoretical predictions and to determine directly in the cell culture how the loss of this gene affected the brain organoid’s further development. “We have shown for the first time that the GLI3 gene is involved in the formation of forebrain patterns in humans. This had previously been shown only in mice,” Treutlein says.

Model systems reflect developmental biology

“The exciting thing about this research is that it lets you use genome-wide data from so many individual cells to postulate what roles individual genes play,” she explains. “What’s equally exciting in my opinion is that these model systems made in a Petri dish really do reflect developmental biology as we know it from mice.”

Treutlein also finds it fascinating how the culture medium can give rise to self-organized tissue with structures comparable to those of the human brain – not only at the morphological level but also (as the researchers have shown in their latest study) at the level of gene regulation and pattern formation. “Organoids like this are truly an excellent way to study human developmental biology,” she points out.

Versatile brain organoids

Research on organoids made up of human cell material has the advantage that the findings are transferable to humans. They can be used to study not only basic developmental biology but also the role of genes in diseases or developmental brain disorders. For example, Treutlein and her colleagues are working with organoids of this type to investigate the genetic cause of autism and of heterotopia; in the latter, neurons appear outside their usual anatomical location in the cerebral cortex.

Organoids may also be used for testing drugs, and possibly for culturing transplantable organs or organ parts. Treutlein confirms that the pharmaceutical industry is very interested in these cell cultures.

However, growing organoids takes both time and effort. Moreover, each clump of cells develops individually rather than in a standardised way. That is why Treutlein and her team are working to improve the organoids and automate their manufacturing process.
Human Cell Atlas

The research and mapping of brain organoids is embedded in the Human Developmental Cell Atlas; this, in turn, is part of the Human Cell Atlas. The Human Cell Atlas is an attempt by researchers worldwide both to map all cell types in the human body and to compile data on which genes are active in which cells at which times as well as on which genes might be involved in diseases. The head of the Human Cell Atlas project is Aviv Regev, a biology professor at MIT; she received an honorary doctorate from ETH Zürich in 2021. ETH Professor Barbara Treutlein is co-coordinating the Organoid Cell Atlas subsection, which aims to map all the cell stages that can be produced in cell culture and then to compare them with the original cells of the human body.

Science paper:
See the science paper for instructive material.

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The Swiss Federal Institute of Technology in Zürich [ETH Zürich] [Eidgenössische Technische Hochschule Zürich] (CH) is a public research university in the city of Zürich, Switzerland. Founded by the Swiss Federal Government in 1854 with the stated mission to educate engineers and scientists, the school focuses exclusively on science, technology, engineering and mathematics. Like its sister institution The Swiss Federal Institute of Technology in Lausanne [EPFL-École Polytechnique Fédérale de Lausanne](CH) , it is part of The Swiss Federal Institutes of Technology Domain (ETH Domain)) , part of the The Swiss Federal Department of Economic Affairs, Education and Research [EAER][Eidgenössisches Departement für Wirtschaft, Bildung und Forschung] [Département fédéral de l’économie, de la formation et de la recherche] (CH).

The university is an attractive destination for international students thanks to low tuition fees of 809 CHF per semester, PhD and graduate salaries that are amongst the world’s highest, and a world-class reputation in academia and industry. There are currently 22,200 students from over 120 countries, of which 4,180 are pursuing doctoral degrees. In the 2021 edition of the QS World University Rankings ETH Zürich is ranked 6th in the world and 8th by the Times Higher Education World Rankings 2020. In the 2020 QS World University Rankings by subject it is ranked 4th in the world for engineering and technology (2nd in Europe) and 1st for earth & marine science.

As of November 2019, 21 Nobel laureates, 2 Fields Medalists, 2 Pritzker Prize winners, and 1 Turing Award winner have been affiliated with the Institute, including Albert Einstein. Other notable alumni include John von Neumann and Santiago Calatrava. It is a founding member of the IDEA League and the International Alliance of Research Universities (IARU) and a member of the CESAER network.

ETH Zürich was founded on 7 February 1854 by the Swiss Confederation and began giving its first lectures on 16 October 1855 as a polytechnic institute (eidgenössische polytechnische schule) at various sites throughout the city of Zurich. It was initially composed of six faculties: architecture, civil engineering, mechanical engineering, chemistry, forestry, and an integrated department for the fields of mathematics, natural sciences, literature, and social and political sciences.

It is locally still known as Polytechnikum, or simply as Poly, derived from the original name eidgenössische polytechnische schule, which translates to “federal polytechnic school”.

ETH Zürich is a federal institute (i.e., under direct administration by the Swiss government), whereas The University of Zürich [Universität Zürich ] (CH) is a cantonal institution. The decision for a new federal university was heavily disputed at the time; the liberals pressed for a “federal university”, while the conservative forces wanted all universities to remain under cantonal control, worried that the liberals would gain more political power than they already had. In the beginning, both universities were co-located in the buildings of the University of Zürich.

From 1905 to 1908, under the presidency of Jérôme Franel, the course program of ETH Zürich was restructured to that of a real university and ETH Zürich was granted the right to award doctorates. In 1909 the first doctorates were awarded. In 1911, it was given its current name, Eidgenössische Technische Hochschule. In 1924, another reorganization structured the university in 12 departments. However, it now has 16 departments.

ETH Zürich, EPFL (Swiss Federal Institute of Technology in Lausanne) [École polytechnique fédérale de Lausanne](CH), and four associated research institutes form The Domain of the Swiss Federal Institutes of Technology (ETH Domain) [ETH-Bereich; Domaine des Écoles polytechniques fédérales] (CH) with the aim of collaborating on scientific projects.

Reputation and ranking

ETH Zürich is ranked among the top universities in the world. Typically, popular rankings place the institution as the best university in continental Europe and ETH Zürich is consistently ranked among the top 1-5 universities in Europe, and among the top 3-10 best universities of the world.

Historically, ETH Zürich has achieved its reputation particularly in the fields of chemistry, mathematics and physics. There are 32 Nobel laureates who are associated with ETH Zürich, the most recent of whom is Richard F. Heck, awarded the Nobel Prize in chemistry in 2010. Albert Einstein is perhaps its most famous alumnus.

In 2018, the QS World University Rankings placed ETH Zürich at 7th overall in the world. In 2015, ETH Zürich was ranked 5th in the world in Engineering, Science and Technology, just behind the Massachusetts Institute of Technology, Stanford University and University of Cambridge (UK). In 2015, ETH Zürich also ranked 6th in the world in Natural Sciences, and in 2016 ranked 1st in the world for Earth & Marine Sciences for the second consecutive year.

In 2016, Times Higher Education World University Rankings ranked ETH Zürich 9th overall in the world and 8th in the world in the field of Engineering & Technology, just behind the Massachusetts Institute of Technology, Stanford University, California Institute of Technology, Princeton University, University of Cambridge(UK), Imperial College London(UK) and University of Oxford(UK) .

In a comparison of Swiss universities by swissUP Ranking and in rankings published by CHE comparing the universities of German-speaking countries, ETH Zürich traditionally is ranked first in natural sciences, computer science and engineering sciences.

In the survey CHE Excellence Ranking on the quality of Western European graduate school programs in the fields of biology, chemistry, physics and mathematics, ETH Zürich was assessed as one of the three institutions to have excellent programs in all the considered fields, the other two being Imperial College London (UK) and the University of Cambridge (UK), respectively.