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Over dinner at Bobby Flay’s Mesa Grill, I was recommending Gordon Shepherd’s book, Neurogastronomy, to a friend, who is a foodie. He seemed really interested in it, having read Herve This’s Molecular Gastronomy and other books like it. I’ll say here what I told my friend.

Shepherd brings with him both expertise and experience on the subject, having actually worked in olfaction for many years. The people he works with are my friends and peers, as I have also worked in olfaction until recently.  The way this book is presented is a model I wish to emulate; it is a  synthesis of both scientific findings and their meaning to us. By combining these elements with clear descriptions of the experiments involved, Shepherd is able to place the mechanics of smell within the context of odor and flavor perception. How the system works, how quality of life can be impaired, possible evolutionary consequences, and ultimately how we can subvert human flavor perception to improve our diet, nutrition, and yes, pleasure. 

Gordon Shepherd has made a huge impact in neurophysiology and in the field of olfaction. I think it is wonderful that he has written this book, to emphasize that olfaction is an important sense, playing a role in shaping human culture by its role in flavor perception. This is a direct counter to the notion that the human (and primate) olfactory system compares “poorly” against other sensory systems because the amount of brain space devoted to processing olfactory data seem so small. It also counters the perception from an olfactory detector consideration, such as that other mammals have both a greater number and variety of odor sensors, and thus as a result that they are better smellers than humans.

For me, I also had the vicarious thrill of seeing people I know depicted in a book meant for a wider audience.

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From the standpoint of a neuroscientist, it was refreshing to see how a distinguished scientists view as the most important pieces of neurophysiological evidence fitting into the concept of flavor perception.  This is the bit of curation that I am such an enthusiast for. We have a wealth of data, and often, scientific reviews are a great place to being reading about a field. Reviews are as much about synthesis of existing scientific threads as much as about historical perspective and charting future research directions (i.e. what hasn’t been yet addressed).  With so much great writing today, having forty or fifty years of experience may not be necessary to provide proper context for a given research environment.

With that said, it is always nice to see someone with the stature of Gordon Shepherd present such a broad picture of the field and to hew closely to underlying research.

He spends the first chapters discussing some anthropology findings, laying the groundwork for the importance of flavor in shaping human culture. It seems that cooking – with its transformation of food at the molecular level and in the unlocking of huge stores of nutrition – provides a huge impetus in humans retaining a strong smell sense. The rest of the book recounts both his own and others’ contributions to the field of olfaction.

His presentation of neural activity is that brain works by encoding and extracting information that can be described as literal, physical patterned activity. Evidence from open brain surgery, to anatomical tracing, to functional imaging supports this idea. In each case,  patterns arise from ephemeral neural activity, grouped into physically discrete locations on the brain. Hence one hears about the visual and audio cortices, the somatosensory cortex, the hippocampus as a site of early memory formation, and so forth.

For the olfactory system, this is also true: at increasing levels of topologic precision, we can say that the main olfactory processing structures include the olfactory bulb, the olfactory cortex, and the orbitofrontal cortex. As we progress to more microscopic descriptions, we can describe groups of active neurons within these structures. The whole point of the brain’s wiring is to funnel external stimuli into combinations of activated neurons.

The connections between these neurons tend to lead to reactivation of the same groups of neurons to the same stimulus. Brain centers located downstream than operate on these patterns, recognizing them, storing them, retrieving them, and matching them. At some point, this stream of information is combined with other sensory inputs (aural, visual, taste, smell, and touch), resulting in higher order, conscious thoughts.

What I say next is not meant as a criticism but as a way to understand why Shepherd is so effective at presenting the science behind “neurogastronomy”. He left out a significant area of research, that of timing. A full description of how the brain works will have to include not only which neurons are active, but when they are active. There is not enough space in such a book to detail the underlying mechanism of smell: the identity of active neurons, how they are connected, and the timing of their activity.

My old boss (among others) was combining smell discrimination-decision making behavior task with simultaneous neural recordings. He, and others, have shown that within a sniff a rat can gain sufficient information to make a decision. This is on the order of a quarter of a second. Such a system likely functions as a time-based code. This is a huge part of understanding how the brain works.

Yet I have to say, it isn’t necessary to Shepherd’s story. Shepherd paints a compelling picture by simply presenting neuronal activity as a pattern, allowing him to describe a huge arc in a few strokes. But this stroke does reveal his thinking; he clearly places a central role in the anatomical organization of the brain, which groups neural activity into patterns. At ever more minute levels, the specific connections underlie the feature extraction processes going on in the brain. In a sense, the fact that neurons, at some point, activate represents the mechanics of actualizing information processing that we had already determined to take place in these neurons, based simply on how they are connected.

Depending on your viewpoint, when the neurons activate may prove important in these processes. Is timing then a peripheral phenomenon, since the most important observation is how these neurons are wired, or could the same wires actually transmit different “information”, depending on the sequence of activity? These are questions researchers continue to spend entire careers answering.

I can imagine a different investigator may have written the same book, but emphasize the ephemeral nature of neural ensembles where the real significance may lie in timing of the activity. In this case, the sequence of neurons firing, how their activity coincide, and the precise synapses activated in downstream neurons are just a few of the parameters that affect perception.

It isn’t a matter of discrediting one versus the other; it is just a point about presentation. In no way am I suggesting that the viewpoint put forth by Shepherd as deficient, merely that he probably made an editorial decision to provide a coherent framework for the edification of non-scientists. I really admire this book, as an exemplar of a rigorous book meant for popular consumption. Most importantly, I feel that he has described the wealth of experimental detail about how current theories of olfaction and flavor perception were arrived at.

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Something close to home. The Scientist and New York Times reports that Nobel Laureate Linda Buck retracted two papers recently. This follows a retraction of a Nature paper from 2001. All three papers featured work done by a post-doc, Zhihua Zou. The retracted papers have no bearing on the work Buck and Richard Axel had performed in identifying the family of G-protein coupled receptors, which won them the Prize.

Rather than focusing on the work in the retracted papers, I would like to explain why, fortunately enough, the retractions do not substantially alter our view of how olfaction works.

First and foremost, independent researchers, using independent means, have found similar results presented in the retracted papers. The main points from the three retracted papers are,

1) Using a genetically encoded neuronal tracer, the paper purported to show that neurons that express the same olfactory receptor connect to neurons that wire to the same brain regions responsible for olfactory processing (Zou et al, 2001).

2) That a marker of neuronal activity, c-fos expression, showed that activity patterns in olfactory cortex is reproducible across animals and are typical for a given smell, a molecule of which is termed “odorant” (Zou et al., 2005).

3) That mixtures of smells activate neurons that respond to the components individually (the pattern of activation is a summation the patterns evoked by single odor components.) (Zou and Buck, 2006).

The peripheral olfactory system can be described as follows. The primary, sensory neurons are situated in the nasal cavity and are responsible for detecting odor molecules. These neurons form connections with neurons of the olfactory bulb. In turn, OB neurons project to “higher olfactory centers”, which includes the piriform cortex.

For the first retracted point, there already exists research showing that connections into the piriform cortex from the olfactory bulb is both convergent and divergent. This can be shown by labeling small groups of neurons in the olfactory bulb, and then watching where the labels wind up. In the piriform cortex, one can see the label over large areas even if the label started out in a confined area in the olfactory bulb, thus showing divergence. A small location in the piriform cortex also receives neurons from all over the bulb (i.e. convergence) when using labels that travel from the cortex to the bulb.

The specific detail offered by the Buck group is that the neurons connecting to piriform cortex share a common origin. That is, the sensory neurons in the nose connect to olfactory bulb neurons that in turn connect in to clusters of physically near neurons within the piriform cortex. The groupings at this level suggest that the piriform cortex could be built from many such groups of neurons. Thus, when an odor molecule activates receptor neurons in the nose, eventually, clusters of activity could be found in the piriform cortex. These spatial patterns may result from the sums of all the receptor neurons that were activated (both these points were covered in Zou et al., 2005 and Zou and Buck, 2006). The spatial organization may reflect an (still unclear) advantage or need for neural processing.

That is a very rough sketch of some basic ideas in mammalian olfaction. As noted, tracing experiments, performed in separate labs with different methods show that there is some structure in where neurons form projections. Whether one can make specific statements linking a response and/or connection to some neurons in the nose is at issue.

One should note that the retractions from Buck lab do not indicate misconduct (yet) – i.e. doctoring and faking of data. The problems could have arisen in analysis. Indeed, Illig and Haberly, in 2003, using the same c-fos methodology to indicate activity, found that the piriform cortex had widespread activation in response to odorant exposure. A “pattern” of activity was absent. Using both electrophysical recordings and optical indicators of neural activity, similarly wide-spread activity was also observed in mice and rats. Even in zebrafish, wide-spread activity within the olfactory cortex analogue was observed. The clustering seen by the Buck group could have arisen by chance clustering of the c-fos signal and could have been enhanced by the analytical techniques they used. I do not know how the data was analyzed to lead to the results published in the paper, but there are mistakes one can commit, without any malfeasance intended.

A note on the methods: there are some significant differences in the way activity is reported with c-fos when compared to electrophysiological and optical recordings. Expression of c-fos is linked to calcium influx in activated neurons. The usual method in evoking this response, to create enough signal against a background, is to expose the animal for 30-60 minutes, to a single odorant. In contrast, the other techniques show responses lasting less then a second (and at millisecond precision) in response to exposure to smells. Further, the chain of events leading from activated neuron to c-fos expression is unknown. For example, how many electrical impulses (i.e. action potentials) in neurons correspond to a given level of c-fos expression? While useful as a gross measure to identify areas of interest, the c-fos technique ultimately lacks some of the advantages researchers need to make definitive statements about smell processing at the actual time scales relevant to brain function.

That is an important distinction: techniques  that are similar to those Linda Buck’s lab used have worked in other labs. The key point is that we can no longer use the tracing results that purported to show connections at 3 structures in the olfactory system. Although we no longer know the specific identities of the connected neurons, the general principle of convergent/divergent connections remain. As for her other conclusions in subsequent papers, there is enough evidence to suggest that the organization of activity in the piriform cortex occurs in the timing of neural responses and not necessarily by their physical locations.  Further, the technique her group used to assess activity has disadvantages in assessing neural activity at millisecond time scales (which is the regime where neurons work.  Thus the findings themselves, although retracted, do not alter at a deep level what researchers think about olfaction.

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