Upinder Bhalla came to Cambridge to read physics, but switched to biology. He took his PhD at Caltech, where he investigated the olfactory system. After a few years, he returned to India to teach and research at the National Centre for Biological Sciences in Bangalore. In 1999, he was awarded the Wellcome Trust Senior Research Fellowship. His project aims to record the electrical activity of hundreds of neurons while delivering precise smell stimuli. He helped to write one of the most widely used neural system simulators called Genesis, and published papers everywhere from Science to Trends in Neuroscience. His passion for regional Indian sweets has led him to name the computers in his lab after them.
What’s art got to do with smell? What are you trying to do here?
Two artists Leslie Hill and Helen Paris approached me with their Wellcome-sponsored “On the Scent” project, which is an installation/performance project to investigate the potential of smell to trigger memories and emotions. I thought it all sounded good fun so I got involved.
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How will the exhibition work?
There will be four chambers: reminiscence, false scents, making scents and on the scent. “Reminiscence” will be a sort of olfactory museum of smells from different times and cultures, designed so that people will encounter a range of familiar and new odours depending upon their age, ethnicity and place they grew up in. For instance, a perfumes from the 1930s and 1940s will evoke memories for older audience members while the younger lot will experience them as “new” smells. Likewise, the smell of Indian cooking spices may evoke memories of home to a London-based Indian, while to a British person it might be reminiscent of the local curry house or trips abroad. This chamber is about how our cultural and ethnic backgrounds affect our emotional responses to smell. Can one smell engender quite different emotional responses from people depending on their background or ethnicity? Does this then lead to varied interpretations of the same event? According to the artists, the primary geographical, ethnic and cultural contrasts will be between British and Indian smells. We also plan to bring this to India to compare responses in the two countries.
What about the false scents?
In the second chamber, all the sensory stimuli apart from smell will tell them that they are in one environment, such as an office, while the smell overwhelmingly communicates, say, the seaside. The artists say they want to deliberately pose the question whether our sense of smell decreases as we communicate more and more through the machine – the virtual – and less from face to face contact – the visceral.
Then people move on to a third chamber where they will work with a perfumer to create a perfume “self portrait”. And we’ll be observing any fragrance portraiture trends among sexes, ages, ethnicities and so on. The final chamber consists of smell-less recording booths, where participants will record any autobiographical smell memories that they would like to share, either those triggered by the smells encountered elsewhere in the piece or simply through thinking about smell and memory.
Did this exhibition feed back directly into your research?
When the artists said they wanted to make it a “travelling circus”, it got me thinking. It occurred to me that we could do highly focused experiments in olfaction. Since we are building an olfactometer, which will make very precise measurements, I thought we could use this travelling circus to capture the way different ethnic groups in a country as diverse as India respond to odour.
Why?
I’m interested in possible genetic drift in human populations. Humans have about a thousand receptor genes that code for molecular detectors of different odorants. But unlike animals that depend on their sense of smell, 70 per cent of these genes don’t work – they are pseudo-genes. I find that very interesting. It’s obvious that they are not of critical survival value, which is why they were lost. If that’s the case, though, then different human lineages might have different patterns of loss. There are some very interesting groups in India, for example, the tribal peoples of Andaman and Nicobar Islands, who have been isolated for a very long time.
Why have humans lost so much of their ability to smell?
It’s not critical for our survival. But then humans are not very old as a species, so it’s a fairly rapid loss and that is why I think there’s some possibility for me to take my olfactometer and do the travelling circus and actually find differences in terms of gene expression – to see how different people respond to different classes of odour. We could then do a DNA analysis of their olfactory genes.
So what exactly is an olfactometer?
It is very difficult to deliver single stimuli, so you have to take a lot of things into account while designing an olfactometer. There are several designs. My current one – and we’ve had four versions so far because it is so difficult – is an air-dilution olfactometer. It first forms a saturated odour by bubbling nitrogen through pure odorant, with glass beads in the bubbler to increase the surface area and eliminate aerosol formation. Then the saturated odour is diluted by a purified air stream. Both the saturated odour flow and the air stream are regulated, so we end up with a known dilution. Other olfactometers dilute the odour in a solvent, or use saturated odour over a dish to increase the surface area so the air over the dish gets saturated with the odour. Some others use soaked cotton wool in an air stream – or even use scratch-and-sniff. Air-dilution olfactometers are generally the most precise.
But surely olfaction is the slowest of all the senses because it depends on the speed of the respiratory cycle. Why is it useful to study it?
Unlike other senses, olfaction is not so important as a primary information-gathering sense, but it is very important in setting the context for many emotions. This is something that the perfume industry takes advantage of. My interest is that olfaction is by far the simplest of all senses. In neural terms, there are only two major olfactory regions in the brain: the olfactory bulb and the pyriform cortex, with a few small accessory structures. This contrasts sharply with the visual system, which in the primates has probably 50 regions in the brain. Olfactory regions, which are in the palaeocortex, are also in some ways more primitive, so they are simpler. For example, the palaeocortex has three layers compared with the neocortex, which has six. Also, the brain circuitry becomes simpler.
This must surely mean that there is something basic going on…
Yes. Olfaction is very interesting in that the primary olfactory region, the olfactory bulb, is almost miraculously similar to the primary olfactory regions of insects, which almost certainly evolved separately. So there is something fundamental about the nature of stimulus in olfaction that is suited for processing by certain brain structures. Olfaction is also very significant in memories. So if you are trying to understand how the so-called higher-order processes in the brain happen – things like learning and associating different kinds of input – it makes sense to start with a system that has a very strong effect on memory. But although the olfactory system is simple to look at in terms of brain circuitry and so on, it is a tricky sense in terms of delivering the stimulus – hence the olfactometer.
Like many other researchers round the world, you’re working on interfaces between computers and the human brain…
The key thing is to find a way to interface neurons in the brain with electronics. We are developing systems for simultaneously recording the activity of many different cells in the brain with sufficient precision in time and space so that you can pick up the activity of individual cells while at the same time recording the activity of many cells.
There are two major issues here: to pick up or transmit signals, and to understand how the brain represents information so that you can make sense of what you see – or if you want to stimulte it, then to find out how you stimulate it in a pattern that makes sense. The latter is the key to understanding how the brain processes information and then stores it.
The goal of this kind of research is to provide real-time control of robot arms in three dimensions. There are applications galore: from people working in hazardous environments to computer geeks who might want to type very fast. Spectacular things have been achieved, such as the work by Miguel Nicolelis at Duke University in North Carolina and his team, who have brilliantly shown how rats and monkeys can control robot arms.
How does your approach differ specifically?
My direction is the opposite one: how do you get input into the brain. Here I’d like to add a word of caution. The brain already has extremely effective input devices – the sheer rate of information upload that it can get through your eyes is unlikely to be surpassed for many, many years, even when the technology for prosthetics is very advanced. But of course when people have damaged eyes, it would make a lot of sense to have this other kind of input. Or it would be interesting to stimulate sensations in the brain that humans no longer have the sensory modalities to experience. This is something which we could do using olfaction. In principle, we could stimulate the olfactory system in patterns that our limited set of receptors can no longer handle and thus be able to have smell sensations that we have not had since we diverged from monkeys.
Why do you think olfaction would be easier to restore than vision?
Restoring vision using neuroprostheses is possible when the cortex is provided with a well-controlled electrical stimulation pattern that mimics the pattern of neural activity commonly associated with vision. Since the visual system is very complex, it is quite likely that a large number of parallel channels of stimulation are required. The olfactory system is much simpler, and hence easier to study by stimulating patterns in the brain – through sniffing an odorant and “seeing” those patterns in the brain.
You went back to India even though you knew the country lagged behind in the infrastructure needed to do world-class neuroscience
From the outside it looks like that, but for me it was a very straightforward and obvious choice that was made even before I left India. My wife, who studied membrane biophysics and proteins and is now at the recently established Institute of Bioinformatics and Applied Biotechnology in Bangalore, is of a similar mind. So when we finished our postdoctoral work, we didn’t have to think twice about returning to India.
When I left in 1983, computers were museum pieces and extraordinarily expensive. Even low-end IBM PCs were hard to get and didn’t work very well. When I returned in 1996, thanks to the information technology revolution here, you could get machines that were only six months out of date. Now you can get them pretty much immediately. Also, centres have started up that are forward-looking. NCBS, for example, is fairly young and is an offshoot of a 50-year old institution-the Tata Institute of Fundamental Research. Other new centres such as the National Brain Research Centre in New Delhi show how change is coming in Indian neuroscience. It’s absolutely true that the neuroscience community in India is very small, but there’s a great deal of enthusiasm.