Steve Mirsky:    Welcome to this special, Nobel Prize edition of Science Talk, the podcast of Scientific American, I'm Steve Mirsky. 

Göran Hansson:         The Nobel Assembly at Karolinska Institutet has today decided to award the 2014 Nobel Prize in Physiology or Medicine with one half to John O'Keefe and the other half jointly to May-Britt Moser and Edvard Moser for their discoveries of cells that constitute a positioning system in the brain. 

Steve Mirsky:    Göran Hansson of the Nobel committee.  O'Keefe is at University College London.  He discovered the so-called place cells in the hippocampus in 1971.  The married Mosers are at the Norwegian University of Science and Technology in Trondheim.  In 2005, they found the other component of the brain's inner GPS system, the grid cells.  After the announcement of the winners, Nobel committee member Ole Kiehn briefly explained the research. 

Ole Kiehn:          This year's Nobel laureates have discovered key aspects of an advanced positioning system in the brain, an inner GPS, that makes it possible to know where we are and find our way. 

                           The abilities to know where we are and find our way are essential to our existence.  For example, how can we know we are in a square in front of the concert hall in Stockholm, and how can we know – how can we find our way from the concert hall to another place in the city, for example the city hall, and how can we store this information so we can find our way the next time we take the same path? 

                           These abilities are governed by activity in the brain, but where in the brain is the positioning system located that allow us to perform these tasks and how can the brain compute such complex intellectual functions? 

                           The work by the Nobel laureates has given us answers to these questions.  John O'Keefe discovered the first component in this positioning system.  He was really fascinated about how the brain can create behaviors, and in the late 1960s, he addressed this problem by recording nerve activity in freely moving rats.  He recorded from an area in the brain called hippocampus, and much to his surprise, he found in hippocampus nerve cells that were only active when a rat was in a certain position in the environment.

                           So O'Keefe called these cells place cells, because a cell was only active in a certain position in a certain place in the environment.  Different place cells in the hippocampus are active in different places, and O'Keefe therefore concluded that the activity of these cells create an inner map of the environment. 

                           The same combination of place cells was active when the rat visited the same environment, but if it visited a new environment, a new combination of place cells would be active.  O'Keefe therefore concluded that the place cells in hippocampus generate many inner maps of the environment which give them information about where we are and how we can recognize new environments. 

                           O'Keefe's discoveries of place cells showed that specialized nerve cells can compute abstract higher brain functions.  His finding had dramatic impact on the study of how the brain creates behavior.  More than 30 years after O'Keefe's original discovery of place cells, May-Britt Moser and Edvard Moser found another component in the positioning system. 

                           They were recording from cells in the entorhinal cortex which is strongly connected to hippocampus, and they discovered a complete new type of nerve cell activity.  A certain type of nerve cells in the entorhinal cortex were active not in one place but in many places in the environment.  Strikingly, when the Mosers drew lines between the places in the environment where the cell was active, they discovered that the activity pattern looked like a hexagonal grid. 

                           They therefore called these cells grid cells.  The pattern of the grid cells is slightly shifted in environment so that the hexagon will cover the entire environment.  So activity in many grid cells therefore provide the brain with a coordinate system that divide the environment into longitudes and latitudes that allow us to keep track on how far we are from the starting point and the turning point. 

                           The discovery by May-Britt Moser and Edvard Moser of the grid cells showed that the brain can create a mental representation of a coordinate system that can be used or navigation in the external world. 

                           Grid cells, together with other cells of the entorhinal cortex, form a connected circuitry with place cells in hippocampus.  This nerve cell network constitutes a comprehensive positioning system and inner GPS in the brain. 

                           Recent works – work in humans have shown that humans also have place-like cells in hippocampus and grid-like cells in entorhinal cortex.  So these findings suggest that we possess a positioning system similar to the one found in rats. 

                           So the discoveries by the Nobel laureates provided a paradigm shift in our understanding of how groups of specialized nerve cells work together to execute higher brain functions.  Their work has opened new avenues for studying how cognitive processes are integrated and computed by the brain. 

Steve Mirsky:    The Karolinska faculty members then took a few questions from the press.  In addition to Ole Kiehn again, you'll hear Hans Forssberg respond. 

Ole Kiehn:          So the question is if other animals than rats have the system and if it's similar to – if birds use this system when they navigate?  That's the question.  What has been shown is that both grid cells and place cells are found in rodents, it's found in bats, it's found in monkeys and now also shown in humans, so it seems to be a system that is in all mammals. 

                           Other vertebrates also have hippocampus-like and entorhinal-like structures, so it might also be found in fish.  Whether it's exactly all the components of this is used in birds is not completely known.  There are magnetic fields that the birds might use for their navigation, but what is characteristic for this system is that it's not dependent on one sensory input, it's a combination of many sensory input that creates the activity in the place cells and in the grid cells.  

Female 1:          I'm a freelance journalist for Channel Radio.  My question is this discovery then what's the significance of that?  Will it indicate that you can find better, for example, hemorrhage and other diseases for the brain? 

Hans Forssberg:         It's very clear that there are many processes in the brain, and this is one function, one process which has been described.  It's not describing the mechanisms of brain disorder.  It's a consequence of a brain disorder. 

                           So you have a brain disorder, like you said a hemorrhage or Alzheimer's we took as an example, and that disease will disturb the circuits, so you will have an impaired function.  So we are on the functional level and the neural circuit level, but not on disease mechanism. 

Göran Hansson:         So again, the prize for a fundamental discovery of how the brain works, likely to give important results and inspiration for research about diseases in the future, but no immediate therapy based on this.  Up there, please.  Question is are there gender differences in the positioning system of the brain [Crosstalk]. 

Ole Kiehn:          I don't know [laughter].  I think that I don’t even know, but I think that the experiments in rats went on in both male and female rats.  I think is that what you're aiming at? 

Göran Hansson:         Hans has information here. 

Hans Forssberg:         So this is just – we don’t know about the particular, the grid cells and the place cells, but we knew about the sense of place and navigation, and there yes, there is a gender difference in humans.  One half of us can navigate better than the other, if you look on an average. 

Steve Mirsky:    Juleen Zierath, chair of the Nobel committee, then spoke with an unnamed interviewer about this year's prize. 

Juleen Zierath: This year's laureates have discovered a positioning system, an inner GPS in the brain that helps us located our place in space and helps us navigate our environment. 

Interviewer:     During the press conference, I got this impression that the audience was a bit surprised of this choice.  Why is that? 

Juleen Zierath:  Well, these discoveries don’t come out of the blue.  It was already in the late 1960s and early 1970s that John O'Keefe made his seminal discovery of the place cells, and 30 years later, the Moser's discovered – in 2005 discovered the grid cells. 

                           So people working in the field and the broader area of science have been aware of these discoveries for some time and aware of the paradigm shifting nature of their work.  So I don't know that it's such a surprise. 

Interviewer:      The will of Alfred Nobel stated that the prizes would be awarded to those that proffer the greatest benefit on mankind.  So how does this prize fulfill this criteria? 

Juleen Zierath:  Right, so that is true for all of the Nobel prizes, and questions about how we are in the world, how we move in the world, how we process this information has been a subject for philosophers and psychologists, behavioralists and experimentalists for centuries.  So now we have some evidence for a network in the brain that allows us to understand our space in the world and how we navigate our environment.  So I think that's a pretty big benefit to mankind, we know much, much more about how we are in the world. 

Interviewer:      This prize is supposed to be for physiology or medicine, which one would you say is more applicable here? 

Juleen Zierath:  This is a prize for basic physiology in a field of neurophysiology.  So we're not on the medical side yet, but really on the basic fundamental physiology.

Interviewer:      And what are the key breakthroughs that make these laureates worthy of a Nobel prize? 

Juleen Zierath:  Well, there's really two parts to this.  So the first is the discovery by John O'Keefe of the place cells, and that happened in the early '70s, and he did some really remarkable experiments.  He was studying the behavior of rats moving freely in a closed environment.  And he was able to put electrodes on the animals, and when the animals navigated or moved through a route, these cells, these place cells were excited. 

                           What he could find is that it wasn’t just one place cell, but it was several of these place cells that worked together in a system.  They were sort of navigational signposts, so to say.  You imagine a map, they're the landmarks.
 
                           And then he could take the rat and he could move it to a new environment, they place cells were also activated, but they were activated in different combinations representing that new environment.  Then he could take the rat, put it back in the initial environment and the rat had a map.  It had a memory, you could say, of the previous route, the place cells fired in the order that they had initially.  So the rat had a cognitive map of its environment. 

                           The second part of this discovery comes 30 years later, and this was by May-Britt and Edvard Moser.  They were also studying the behavior of rats in a closed environment, but they made a larger field for those animals to move.  They were also studying nerve cell activity in a region of the brain called the entorhinal cortex. 

                           What they found was when these rats navigated the environment to forage for food, they saw an astonishing activity.  And when they drew lines between the visual input of this activity, they found that this activity represented a hexagon, and they could see that it was a grid-like structure. 

                           In other words, the rats were forming a navigational platform and this was used for moving and for judging distances.  So the third part of this is that understanding that together, the place cells and these grid cells work as a neural network.  We have the grid cells to navigate our environment and we have the place cells as signposts for us to help us find our way in the environment. 

Interviewer:      So what – was this recognized as a breakthrough at the time? 

Juleen Zierath:  It was astonishing, absolutely.  So as I mentioned, the breakthrough moments was first of all the discovery that there were place cells, that's one big discovery.  The second was that these place cells worked in different combinations, but that combination was always the same when the animal was in the same environment. 

                           The third was that this grid-like structure, this navigational field was completely unexpected, and then again, putting it together with the circuit between the entorhinal cortex and the hypothalamus, understanding this network for us to code our information on our place and space and our navigation in that space. 

Interviewer:      So how would you try to explain the importance of this prize to a young person, let's say an 11-year-old full of curiosity? 

Juleen Zierath:  Well, I'm hedging that your parents take you on a vacation during summer break, and you're going to go visit an exciting city like Stockholm.  And you've never been there before, and so the first thing you do is you take a map from the hotel, and you're going to help your family find the Vasa ship. 

                           So you have landmarks on the map, it could be the city hall, could be the concert house, it could be the palace, and the Vasa ship.  Those are like your place cells, because as you pass those landmarks, they recognize your place in space. 

                           The other thing you need on that map is longitude and latitude.  You need to find a way to navigate to the Vasa ship in a very efficient way, and the grid cells function like that navigational chart.  They help you judge your distance and help you find your way.
 
                           So the remarkable thing is that we don’t need to have the map in our hands.  We have these maps in our brain, and so I would describe it that way.  Thanks to our grid and place cells, we don’t have to walk around with a map to help us find our way each time we visit a city, because we have that map in our head. 

Interviewer:      Now if you turn our attention to the laureates, who are they? 

Juleen Zierath:  Well, we have John O'Keefe and he was born in the US but he's also a citizen of the United Kingdom, and we have May-Britt and Edvard Moser, who are Norwegian citizens working in Trondheim. 

Interviewer:      I'm thinking of the work of Mr. O'Keefe, he – it was like, in the '60s.  Do you know what he's working on now?
 

Juleen Zierath:  You know, he's still an active researcher and he still runs a lab working on technology advancements to study animal behavior, and also understanding how the brain still computes its information by understanding place cells and grid cells. 

Interviewer:      And personally, what makes you so enthusiastic about this prize? 

Juleen Zierath:  I think it's really fascinating, and a little story.  This summer, I went to visit my grandparents' cottage in northern Wisconsin, hadn’t been there in 30 years.  Hadn’t been there at all.  I found myself at the cottage, I could find every single play – childhood little hideout that I had when I was a kid, I could navigate the environment, remarkably, since I hadn’t been there in 30 years.  And I realized, thanks to my place and my grid cells, I was able to find my way and have a great summer holiday.  So I think without these cells we'd have a really hard to survive. 

Interviewer:      And finally, has the Nobel committee been able to get in contact with the laureates? 

Juleen Zierath:  Well, Göran Hansson had a conversation with May-Britt Moser and she was in a lab meeting, was able to take his call, was delighted, had to sit down, have a moment of pause.  And she, of course, wanted the press release in her hand because she wanted real evidence.  Her husband just stepped on an airplane to go to Munich, and he doesn't know.  So he's sitting on an airplane and all this is happening without his knowledge.  

                           John O'Keefe, we found him as well, he was at home, and he was very delighted, looking forward to coming to Stockholm in December. 

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