Updates from Dr. Südhof: Celebrating 20 Years Highlighting Science and Medical Research

Back in 2007, Science Matters (then called What A Year!) highlighted the work of geneticist and neuroscientist Dr. Thomas Südhof. At the time, Dr. Südhof and his team at the University of Texas Southwestern Medical Center and the Howard Hughes Medical Institute had identified a new class of proteins called neurexins. Neurexins are found at the border where two neurons meet, known as the synapse. They are called neurotransmitters because they transmit messages to facilitate communication between two adjacent neurons. Specifically, neurexins bind to proteins on the other side of the synapse, called neuroligins.

Figure 1. Neurexin on the pre-synaptic nerve terminal binds to neuroligin on the postsynaptic nerve terminal to facilitate communication between the two neurons across the synapse.

[Source: https://commons.wikimedia.org/wiki/File:Cartoon_of_neurexin_and_neurolign_interaction.png]

Soon after the What A Year! article was published, Dr. Südhof moved to Stanford University where he has worked ever since. He won the Nobel Prize in Physiology or Medicine in 2013 for his work understanding the role of neurotransmitter release in the brain. Recently, Dr. Südhof spoke with Science Matters again to discuss his career over the last two decades since this research was published.

Science Matters (SM): Where has your research taken you in the last 20 years?

Dr. Thomas Südhof (TS): To talk about this, I think it’s important to give some general background. It is not a surprise to anyone that the brain is a very complex organ. The brain is complicated because there are many cell types that each develop into a large number of subtypes. Understanding how the brain works and processes information, and what happens in diseases of the brain, continues to be a major challenge. Although there has been a lot of research on the brain, we still only understand very little. 

Neuroscientists have different ways of approaching the study of the brain and diseases of the brain. Some study the whole organism, taking images of the brain during certain activities or recording the activity of brain cells. I take the opposite approach. I try to look at individual molecules in the brain and understand how they work and how they contribute to overall brain function.

Specifically, I study how nerve cells in the brain talk to each other at synapses, the contact points and communication nodes between nerve cells. Any individual nerve cell can have thousands of synapses. Information is transferred from one neuron to another across the synapse, and multiple neurons can be connected to form networks or circuits. Synapses process information, but they also change it. In many ways, they are the basic computational unit of the brain. 

In my initial work, I wanted to understand how a nerve cell sends out a signal that another nerve cell recognizes. This process is called neurotransmitter release, and it’s the discovery of how that process works that led to the Nobel Prize. Although we now understand how neurotransmitter release generally works, there are still many questions that remain and many people are working on them.

My lab doesn’t work on that question anymore. I changed direction even before the Nobel Prize. Now I’m focused on understanding the molecular basis for the synapse as such. In other words, how is it that one nerve cell can connect to another nerve cell via the synapse? And how are these synapses different depending on which nerve cells are involved? This process is the basis for the formation and maintenance of neural circuits. There are trillions of synapses in the brain, and they all have different properties. This is also important for the development of brain diseases, because synaptic connections are a primary point of vulnerability. This new question has been more challenging than I expected. We’ve made some progress, but not enough.

SM: What have been some of your key findings?

TS: From our work so far, we hypothesize that at the synapse, as the connection point between neurons, there is a link between the pre-synaptic and post-synaptic sites. We think that this link consists of molecules on each side of the synapse that interact with each other. These molecules are called adhesion molecules because you can make them stick to each other when you study them in cells, but that is not their function. Their function is to allow the pre- and post-synaptic sides to send molecular signals to each other. Neurexins, which we discovered many years ago, are an important class of these molecules but they are not the only ones.

Despite our years of research, there is still a lot of uncertainty and confusion around these molecules. The brain is complex, and every synapse in the brain is complex, and the molecules around the synapse are complex. For example, one molecule, like neurexin, binds to multiple other molecules that bind to something else and so on, creating a molecular network with its own degree of complexity. We suspect that disturbance in these networks leads to disease.

Our goal now is to cut through this complexity to determine which pieces of these molecular networks are actually important. We have so much information now with improved technologies but it can drown out the signal of what’s actually important. That’s one of the biggest challenges in contemporary science. In short, our goal is to understand how synapses are organized. That’s what we’ve been doing for the past 20 years.

We have made advances. Neurexins are now known to be expressed in many different forms due to genetic changes that create many similar but different molecules. We’ve found that these molecules have different functions, and that this is important for organizing synapses. We’ve also identified other molecules that interact across the synapse. Now, we are trying to figure out how these different molecules work together as teams, and which ones are most essential. Some of this research can be done in humans, but we also need research in mouse models and cells.

I’m excited about the potential opportunities for discovering how nerve cells organize synapses with specific properties to form brain circuits. I find this absolutely fascinating, and also daunting. I hope that by making progress on this question, I can contribute more to our understanding of diseases of the brain, which I believe involve the organization of synapses.