Stanford Medicine Newsletter Updates For the Local Community

 

Thomas Südhof, MD

Insights in cellular communication

Sudhof receives his prize at the Dec. 10 ceremony at the Stockholm Concert Hall.

   

Your focus is on basic science, but what you learn in the lab could be very important to helping understand and treat diseases of the brain. Your research related to autism is a good example. Please tell us more about your work in this area.

We identified a series of genes that enable the communications of neurons with each other at synapses, which are the connections between neurons that allow them to talk to each other. It turned out that these genes were mutated in autism, providing an unplanned serendipitous insight into autism. Among others, this led to my friendship with a Massachusetts family with two sons with autism caused by mutations in one of the genes we identified, motivating me to think more deeply about the relation of our work to autism. Currently this is the most active part of our work, and we are enthusiastic about the possibility—remote as it may be—that we can contribute to a better understanding of how an impairment of the communication between neurons may produce autism.

How will your research on synapses help us understand disorders such as Alzheimer’s and Parkinson’s?

Synapses are the most important attributes of a neuron. They connect neurons to networks and circuits, and represent not only the point at which neurons communicate with each other but also the most fundamental information-processing unit in the brain.

Enormous advances in human genetics over the last decade have given us tremendous information on what gene mutations predispose to these diseases, but we do not know why. There are many very expensive clinical trials being conducted based on hunches, on wishful thinking. These trials will cost more than the basic research that prompted it and do not have a very high chance of succeeding. People are going to ask themselves, “Why are we doing this?”

This is where synapses come in: From the little we know about these diseases, synapses are centrally involved. But we do not really understand synapses, and we certainly do not understand what happens to synaptic function in these diseases that may produce symptoms. We need to invest in the fundamental biology of the brain, in understanding how the brain works and how synapses work, in order to understand how the function of the brain and of synapses goes awry in neurodegenerative diseases and in order to develop rational drug targets. I hope our work, among those of many others, can contribute to such an understanding that is a prerequisite for developing therapies.

This is painstaking research, but you have said you are convinced it will eventually lead to new therapies. What makes you so confident that will be the case?

I am optimistic because this is a model that has worked in other diseases. Treating hypercholesteremia (high cholesterol) with statins has revolutionized cardiovascular medicine—
it was entirely based on the non-translational, curiosity-driven research of scientists trying to understand cholesterol biosynthesis. Similarly, unraveling the genetic pathways of cancer has led to the first rational therapies.

This is the way to go: First figure out the biology, then design treatments. I am optimistic that the same can be done for brain diseases.

Why is basic science important, and how can we help build support for it?

Without curiosity-driven work that aims to understand a biological question, we will not understand how the process addressed by the question becomes impaired in a disease. In terms of helping to build support for investing in knowledge, I think we scientists have to start with reforming ourselves. We need to be more honest about what we do, exaggerate less and most of all clean house. We need to ensure that the work which is published is actually true and not just a hyped piece of complex experimentation that in the end means nothing, and we need to pay more attention to being held accountable that what we do is solid and reproducible, instead of sexy and fashionable. If we as scientists want to espouse the value of truth—which is the ultimate measure of all scientific activity—we have to make sure that this is the value we reward and promote.

In the end, scientists are responsible not just for producing scientific literature but for producing literature that is correct and reproducible—a responsibility that we have often recently failed to fulfill.

Is there one vivid memory that stands out from the Nobel ceremony in Stockholm?

The most vivid memory from the Nobel ceremony for me was walking onto the stage guided by the beautiful music played by the orchestra, surrounded by fresh flowers that had been flown in from Italy from the city in which Alfred Nobel had died, and facing not only the assembled audience in the theater but also the previous laureates who had been invited as well as the representatives from the various Nobel committees and the royal family. A very moving moment indeed! 

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