Understanding the developmental process for the creation of different brain neurons may provide a recipe for how to engineer stem cells that can replace these neurons in neurodegenerative disease. This is the aim of the work of Thomas Perlmann of the Department of Cell and Molecular Biology at the Karolinska Institute in Sweden.
“The brain consists of many billions of cells, including many hundred different classes of neurons,” he explained. “A challenge in developmental neuroscience is to understand how this vast diversity is generated. This seminar presents our research on brain development, focusing on dopamine neurons as a model for neuron specification. This class of neurons has essential functions in movement, memory formation, attention and reward responses. Dopamine neurons are also important in disease; most notably, they degenerate in patients with Parkinson’s Disease.
He explained that the work focuses on very fundamental biological questions tracing the developmental process from an egg to clearly identifiable cells, tissues and complex organisms in the human body. “It’s an amazing process and how it works concerns thousands of scientists around the world.”
There are 80 billion neurons in the human brain. There is also huge diversity – with hundreds of different classes of neurons doing different things. How they work is a fundamental question in brain development.
Perlmann focused on his group’s work on dopamine-neuron development and how it relates to the basic understanding of brain development. “This research is proving essential for new strategies for using stem cells to treat Parkinson’s.”
Dopamine is a neurotransmitter (or chemical messenger) – a signalling molecule that is able to talk to other neurons via synapses. It’s produced in the ventral midbrain in the substantia nigra and ventral tegmental area of the brain. Many symptoms in Parkinson’s Disease, the second-most common neurodegenerative disorder after Alzheimer’s, are caused by dopamine death. Dopamine is responsible for movement and co-ordination and loss of these neurons are typical symptoms of Parkinson’s. Perlmann described dopamine as a simple molecule, that is easily derived and exists in all animals that have nerves. “Evolution has selected it out as a suitable molecule to interact with receptors.”
Understanding how the body develops dopamine neurons in the first place is key to understanding how they can be regenerated.
He explained that initial studies were done in this area in Sweden in the 1980s. The idea then was to use aborted foetal brain cells but it was hugely problematic – they were hard to reproduce consistently and, of course, there were major ethical issues involved meaning that this work would never reach many patients.
“The answer is stem cells – primitive cells that exist both in the adult body and also in development, and can form differentiated cells,” he explained. “The most important are the embryonic stem cells which are the most primitive and have the ability to form every cell type in the body. Stem cells can also be artificially induced and cell lines can be maintained in laboratories.”
“How stem cells can be manipulated in a culture dish to form dopamine neurons is therefore a problem that occupies many scientists. It requires understanding the manipulation of cells and how they develop.”
The work is mostly in mouse models and uses single-cell RNA sequencing which makes it possible to trace the trajectory of events.
In early development, cells don’t know which neuron to form and respond to orders received.
Perlmann described the development of the central nervous system and specifically signalling centres which translate into a patterned expression of transcription function that guides what cells should be copied and turns genes on and off.
“In the laboratory it’s possible to characterise the signalling and regulation transcription function to understand the sequence of events and molecular architecture.”
The work this far has identified important dopamine-transcription factors including Lmx1a – master regulator of dopamine neuron specification; Nurr1 – a major executor of genetic programming to express dopaminergic properties; and, Sox6, the most recently identified, and a key regulator of dopamine-neuron diversity.
An important early success was also the revelation of unexpected bifurcation (branching) in the developmental trajectory of dopamine neurons.
“Dopamine neurons come in different flavours,” said Perlmann. “They have a common developmental origin but become different with different targets and functions. There is also major diversity between dopamine neurons with up to 30 000 mapped with some more highly sensitive and vulnerable. Our ongoing work is to elucidate this diversity to help us to understand more about the selective vulnerability of certain neuron types in neurodegeneration.”
“This may provide clues as to why some neurons are more vulnerable than others to degeneration,” he added.
Talking Nobel
Perlmann has also worked for many years as Secretary General of the Nobel Assembly awarding the Prize in Physiology or Medicine. He is also a member of the Nobel Committee. He provided behind-the-scenes insights into the processes involved.
“The Nobel Prize is important because of its reputation and global influence,” he said.
He emphasised that decision making about the awards is bound by the wording in Alfred Nobel’s will (one of the most famous in the world and contested by his family) which denotes that the prize winner “shall have conferred the greatest benefit on humankind”.
“The science prizes are centred around discovery, invention and improvement – not for an outstanding career,” he added. “The mix of prize areas is synergistic, there is very thorough investigation (and few mistakes), and there is an impressive track record of winners – including Curie, Planck, Einstein, Bohr, Watson and Crick, and Fleming.”
He also mentioned recent examples. Svante Pääbo won the 2022 Prize in Physiology or Medicine 2022 for his work in mapping genetic sequences of Neanderthals and identifying a previously unknown hominid – Denisova – providing extensive additional knowledge on critical evolutionary events in history.
As well as the awarding of the 2023 Prize in Physiology or Medicine to Katalin Karikó and Drew Weissman for their groundbreaking discoveries concerning nucleoside base modifications that enabled the development of effective mRNA vaccines against COVID-19 “which saved millions of lives in the biggest health crisis in modern history”.
“The celebration of the individual emphasises that individuals can make a difference and can inspire. It’s about breakthroughs that stand the test of time. We are also very focused on enhancing diversity – in making the process open and inviting. There has been a clear exponential growth in female scientist recipients but there are still not enough nominations from different parts of the world and this needs to improve.”
“It’s an enormous amount of work with thousands of pages to read,” he added.
He also focused on the important outreach component. This includes Nobel Symposia and the Nobel Prize Dialogue and is an essential component of the Nobel in Africa activities hosted by STIAS. These have included vital topics of global interest and “can benefit science-based thinking and fact-based decision making which is very important in our time”.
Michelle Galloway: Part-time media officer at STIAS
Photograph: Noloyiso Mtembu