Transcript from an interview with the 2004 Nobel Laureates in Physiology or Medicine, Richard Axel and Linda B. Buck on 11 December 2004, during the Nobel Week in Stockholm, Sweden.
Welcome to meet the Nobel Laureates in Physiology or Medicine 2004, Richard Axel and Linda Buck. First of course like everyone else, congratulations to the prize. You have heard this millions of times in the past days I suppose. This is the afternoon, the day after the big event, so what about the big event yesterday, what are the most memorable moments of the day, Linda?
Linda Buck: The whole thing was very dramatic and unusual, and it was wonderful to have my family and friends there. It was a once in a lifetime experience.
Richard Axel: I thought that the whole day, the ceremony, the formalism of the ceremony and the grandeur of the evening added a spectacular dimension to what we do, and what we do is try and understand how the world works, how the brain works and to have our work, which we do on a daily basis, celebrated in so grand a fashion, really added a very nice dimension.
One of the things that really strikes you when you read about your science is the huge proportion of one genome that is used for constructing the nose or the olfactory system. Linda Buck, how come, why do we use so much of our genome for the nose?
Linda Buck: I think the way evolution works is that if something happens and if it’s useful then it remains in the genome. I think that during evolution of the sense of smell, multiple genes were made, it was advantageous, and they were capped, and you see that some of the genes are disappearing, there are remnants of genes encoding candidate pheromone receptors in humans and those genes are for the most part intact in mice and most of them have become pseudo genes in humans. Now in addition to that though it does seem that in certain invertebrate organisms there are also very large gene families that are used for smell and so it does seem to be a strategy that has worked, perhaps been developed independently in different organisms …
But happened to be exactly the same systems, in …
Linda Buck: Yes, but the genes are not really related, they’re genes that encode proteins of the same type but are really quite different. So it does seem to be a strategy that’s perhaps been developed independently several times.
Was the sensory organ maybe the first … When you look upon evolution, the way to perceive, to react to the external world, chemotaxis came long before phototaxium and maybe phonotaxis if there is any phonotaxium in the biological world. Is that the right, that the smell, the senses of smell was the first one?
Richard Axel: Chemosensation as you say certainly is the first one. I mean back, every organism, even the most primitive and humble bacterium have to have a way to respond to sense what is in the world around them because that determines how they are going to survive, it determines what their food supply is, how they have to metabolise their food, it determines aversive environments. So all organisms have to have a way to sense the chemical environment and the way they sense the chemical environment has evolved and so we indeed sense it in a different way than does a bacterium but the principle of communicating and responding to the environment is very primitive.
When we come to higher, I shouldn’t call them higher or lower organisms but more complex organisms …
Linda Buck: You’ve got that from anthropology, is that right?
Anyhow, how is this perception of the chemical environment, how is it mediated into action, how can it be translated to action? What mechanisms is life using?
Linda Buck: I think in mammals and also in many invertebrate organisms the information travels through a series of relay stations, if you will, in the nervous system and that allows the information from hundreds or a thousand different receptors to be organised in progressively more sophisticated ways and also in different ways. In the mammalian cortex what we see is that there are distinct anatomical areas in the olfactory cortex that are getting information from the odorant receptor family in the nose and those different areas of the olfactory cortex send information to different areas of the brain. We think what maybe happening is that the information from the receptors is being organised, combined, or perhaps modulated in different ways in those different areas before being sent on to yet other brain areas. This parallel processing of information is something that is seen in other parts of the nervous system as well so you can take the same sensory information from the external world and then you can process it in different ways in different parts of the brain to use that information for different things.
And how do the animals or we perceive all this process? Is it through emotions?
Linda Buck: The information is targeted to different parts of the brain and some of those structures in the olfactory cortex send information on to higher cortical areas, both directly and indirectly through the thalamus, but in addition there are some parts of the olfactory cortex that send information to the hypothalamus and certain parts of the amygdala and those are parts of the brain that control physiological effects, emotional responses and instinctive behaviours. In fact, we think that using the sense of smell, and using molecular approaches, we can gain access to neurons and neural circuits in those very primitive parts of the brain and perhaps begin to obtain information about the neurons and the neural circuits that control instinctive behaviours and emotions.
Does that mean that the olfactory system is also sending signals to the brain that we are not aware of, through unconscious levels of our brain? What do you think Richard Axel?
Richard Axel: That’s a hard question to answer; I mean how do we know that there is the unconscious recognition of scent? We do know, as Linda pointed out, that smell is recognised by cells that project to different areas in the cortex and some of those areas, some of those areas are new brain, cognitive brain and others are old brain, emotive brain. One might think that the odours that activate emotive brain might illicit emotions and innate behavioural responses and neural endocrinal responses without the conscious awareness of those signals. For instance, in animals we know that certain odours can reorganise the time of puberty, can reorganise the menstrual cycle and can illicit or prevent mating. There are studies in humans which are far more difficult to control to suggest that there are olfactory driven changes in the menstrual cycle, there’s a very famous study out of Chicago suggesting that women in a dormitory tend to synchronise their cycles and that’s thought to be olfactory, but those studies are psychophysical not biophysical and they’re much more difficult to prove with certainty.
What about more everyday life events, is it possible that fear can smell and happiness can smell? That we can register emotions in the room without being really aware of it? Is that a too spectacular question?
Linda Buck: People talk about it, I think more in literature than in science, the smell of fear and so on and I don’t know, I think maybe that has to do with components of human sweat or it’s not really, it’s not something that we investigate really and I suppose …
But in just …
Linda Buck: … maybe in the future.
Because in one of your Nobel lectures or Nobel symposia, you talk about your great interest in trying to elucidate how subordination maybe mediated through smells and also aggressiveness and …
Linda Buck: We are actually looking, using mice, we’re using odours that have particular effects on the animals, we’re just starting to do that now. We’re looking at activation in the brain by a fox odour that causes a stereotype fear response. We’re also looking at effects of different kinds of odorants on the behaviour of the animal and looking at parts of the brain that are activated and we do see that mice don’t like skunk odour any better than we do and there are quite dramatic behavioural differences between their responses to skunk, skunk, fox odour and vanilla so they’ll actually try to get to an input tube that’s, through which there’s vanilla odour and they try to hide from the skunk. They try to hide from the skunk and in response to the fox odour; they just become paralysed with fear.
Do we know that useful things tend to be preserved throughout the biological fear and maybe …
Linda Buck: That’s right and it’s clear that in the hypothalamus … The hypothalamus is basically the major control centre of the brain, it’s very primitive, it’s there in animals, it’s there in human and it’s highly conserved in its structure and also in the genes are expressed there and in the neural circuits and most, if not all, instinctive behaviours and emotional responses are controlled by the hypothalamus.
And the hypothalamus has a direct contact with the nose?
Linda Buck: There are inputs from, yes; there are inputs from the nose. The hypothalamus actually collects information from all sensory systems, from the other parts of the brain and from the body. It gets input not only from the nervous system, that of course connects the entire body but also through the bloodstream. It measures the temperature, it measures the composition of the blood, it measures sex hormone levels, it controls the menstrual cycle, it controls the stress response. So it’s basically the main control system and of course because odours can cause stress, fear, pheromones and maybe some odours can control sexual behaviour, we can use the olfactory system to try to gain information about those circuits and start dissecting the neural circuits and the individual neurons including the genes that they express, that control those very basic emotional responses and behaviours. That’s where we’re going next.
Another fascinating information that comes from your science is how the olfactory system is translating scattered molecules of sense into an organised map in the brain, it turns into a physical map, Richard Axel, but who is watching the map inside your brain? How do you make sense out of a physical map from these molecules?
Richard Axel: That’s a central issue that neuroscientists would like to address and have been attempting to investigate for a very long time as you’ve heard me put it before. This is a central issue in all senses that is the way… There seems to be a conceptual thread that runs through the different senses and that is that in olfaction as well as in vision the image, whether it be a chemical in olfaction or a visual image in sight, is very complex and it needs to be deconstructed into its components before it can be re-established in the brain as something meaningful. So in vision for example, the individual components of a visual image, that is colour, movement, edges, form texture even at the level of the retina in the eye are deconstructed and carried to the brain by parallel pathways. They are relayed in different regions of the brain so there are regions of the brain that are responsive to movement and not colour, other regions responsive to edge and not movement and at some point, there must be an area which consists of ensembles of neurons that can put this information back together. Now the analogy to the olfactory system as a consequence of the efforts of a number of people including Linda, suggest that you transform chemical space into brain space in the very same way that a given odour, even a single molecular species in an odour, will have the capability of fitting into multiple different receptors and those receptors project to different points in the brain so that those points, the receptors that an odour can interact with and the points which they activate in the brain, form a signature and then as you point out, you’re left with the problem.
Who is watching?
Richard Axel: The problem of who looks down on these points? Who listens to the music, who sees the activation? As I’ve put it before, it’s an old problem, it’s the problem of the ghost and the machine and philosophers have been addressing this problem now since Plato.
Linda Buck: I think this is a challenge for neuroscience in the future and it’s been recognised for a very long time that we do not know how it is that neurons firing in different parts of the brain, active in different parts of the brain, somehow constitute a perception, a percept because it’s clear that not all the information is going to come together in a grandmother cell and when that cell is activated you think “grandmother”. There are indeed neurons that are activated through, in many different parts of the brain and somehow that constitutes a cohesive perception.
But do you really think …
Linda Buck: And there’s nobody looking, it’s the way it works. There’s no one who will be looking, it’s the way the brain works, and I think that it is a scientific problem in terms of how physically that might happen but it’s also a philosophical problem, a conceptual problem because I think it’s difficult for scientists to conceptualise how it is that neurons that are dispersed in different parts of the brain could form a percept and it could be that it’s just going to take some kind of a conceptual or philosophical step for people to say, That’s not a problem, we accept that.
So, the big enigma, our consciousness arising, is just that that is consciousness, all these things that happen in the brain together?
Linda Buck: Yes, it’s just very hard for people to accept that.
Richard Axel and Linda Buck, thank you very much for sharing your time and your fascinating thoughts and ideas about your science with us. Thank you.
Linda Buck: Thank you.
Richard Axel: Thank you.
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