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'If you can construct tissue that recapitulates lost circuitry, you could possibly repair damage'

Do you believe you can take this ahead from ferrets to humans and other primates?

There is a lot of evidence that in humans too such rewiring happens all the time...

Like in phantom limbs? (Phantom limbs are the limbs that amputated people, or even people who lack those limbs from birth, imagine they possess)

The sensation of phantom limbs is due to one kind of plasticity. Our work relates to a slightly different kind. In congenitally blind people who do not have eyes due to some birth defect, the visual cortex doesn't sit empty. In fact, if you do functional imaging studies, you find visual cortex now engaged in audition or even, in blind people who have learnt Braille, in Braille tasks or certain kinds of tactile tasks.

All these have remained anecdotal observations. We have never understood why and how this happens. But our experiment provides some understanding of these phenomena.

Similarly, in congenitally deaf people -- people who don't have a cochlea from birth due to a birth defect -- the auditory cortex ends up mediating vision. More generally, I certainly think that the reason why even the brains of identical twins are not alike in every way is because they never go through the identical environment.

What does your work imply for the world of medicine?

There are two kinds of extensions that we begin to speculate about. One is to promote ways by which healthy cortex can take on functions of diseased or damaged cortex. What our experiments really show is that a part of the brain, at least early enough in development, can take on new functions. And these new functions are strongly dependent on the nature of input.

The trick is to control the growth of new input into a new part of the cortex. And that requires an understanding of the molecules that make wires grow from one part of the brain into another. Some of our effort now is devoted to finding out the molecules and genes that are themselves regulated by (nerve) activity.

Development is an indivisible story of intrinsic and extrinsic factors. There is no such thing as a gene acting independent of an environment or an environment writing on a blank slate. There is always some structure that one writes on.

Our experiments show too that the auditory cortex is not entirely rewritten to be a visual cortex.

We want to understand the molecules and the genes that are regulated by activity so that we can, some day, be able to alter certain kinds of inputs to brain regions that can then do new functions.

A second extension has to do with making cortical implants. If one has a stroke or a tumor, one loses a part of the brain. If a part of the cortex, or any part of the brain, is lost in an adult, it never regenerates. Our work shows how neuronal connections self-organize. We should be able to grow in a dish a network of neurons that is similar to a part missing from the cortex, and be able to implant it so as to recover lost functions.

But recently hasn't there been talk of growing neurons in the brain?

The evidence for new cells in the adult brain is very limited, and it is not clear that they are doing anything useful. There is overwhelming evidence that all the cells we get in our cortex, or at least the vast majority of them, are present before we are born.

A few regions of the brain, like the hippocampus (crucial to memory function), and perhaps the cerebral cortex, may get a few new cells. But it is not clear that they are not repaired cells as in which the DNA has been repaired or damaged (which is why they have taken up the markers that supposedly mark new cells); and there is no evidence that they have been incorporated into functioning circuits.

Dr Elizabeth Gould at Princeton University has done some work on this, hasn't she...?

That's certainly exciting work, but, as I said earlier, we need to know more about whether the cells are indeed new. And whether there is a significant fraction of new cells.

Out of billions of cells in the brain, if you find five cells that are new, you know, it is not a significant fraction.

The evidence so far is that the vast majority of cells that our central nervous system and our cortex has is what we are born with. Of course, during development they grow processes, they grow connections that venture out and make networks. But if you lose a part of the cortex at any time, that's gone forever. The only recourse is rehabilitation.... when an existing part of the brain can take on new function as a result of learning or practice.

But if you can construct tissue that recapitulates the circuitry that has been lost, and if you can figure out a way to implant it in the cortex, that is an exciting possibility by which you could actually repair the damage.

There is, in principle, no reason why this can't be done, because our work suggests that the pattern of activity can make specific circuits self-organize in a piece of tissue. And that's something we are very excited about. An immediate lesson on this is that one should be able, by providing patterns of activity to neurons grown in culture on biopolymer substrates, to make circuits that can reasonably approximate lost circuits in parts of the brain.

A lot of work has to be done. I don't want to hold out the hope that tomorrow we can repair brain damage due to disease or a tumour. Looking deep into the future, however, this is the greatest possible impact of our work -- that one can grow brain circuits based on the pattern of input activity.

But there has some discussion that multiple inputs together make for the function of different parts of the brain. Something based on the chaos theory? Isn't there anything in that...?

Certainly. Any piece of the brain, any piece of the cortex, must rely on multiple inputs and outputs. However, there are some key inputs and some key outputs. Take the visual cortex, for example. And if you take the primary visual cortex, the key input has to be from the thalamus.

One of the key outputs is to motor (movement) regions responsible for orienting or eye movements or for foveation -- bringing a piece of the visual world into the most sensitive part of the retina, the fovea.

A fundamental part of the primary visual cortex function is the connection to the colliculus, which moves the eyes. But if you have damage in a part of your primary visual cortex you do not see in that part of the visual space.

If you can have an implant that reasonably approximates some of the circuitry and does two things -- give you a sense of objects and shape and make you able to move your eyes so that some other part of the cortex can focus there -- then you have a significant improvement.

How did you get into this field at all?

I'm trained as an electrical engineer, all my degrees are in engineering. But I'm now a neurobiologist.

Engineering from where?

I did my B Tech in Electrical Engineering from IIT Kanpur in 1974, then went on to do my PhD from Vanderbilt in 1978. I was a postdoc at SUNY, Stony Brook, in the department of neurobiology after that, then at Yale as an assistant professor. I've been at MIT since 1986.

How about your family? You are married, aren't you?

I'm married to Abha and we have a son, Samir, who is 16.

Is your wife also an academician?

She is a historian of science.

And how do they view your work?

I don't know, you have to ask them! But they follow my work quite a bit, as I follow theirs!

Abha is a historian of modern physics in India. She is writing a book on the major Indian physicists of the first half of the 20th century -- Raman, Saha and Bose and the impact of society, politics and culture on their work. So we stay in very close touch with India.

Do you think neuroscience is really a rewarding field for students?

Of course! There are very few times in the history of a field that you see so many opportunities in front of you. And neuroscience is certainly going through such a phase.

What are your future plans?

I am chair of my department here, and I intend to continue doing research and teach. I do hope to return to India at some point however and do something useful.

What could you do in India? It is rather difficult for researchers here, isn't it?

It is certainly difficult in India to keep pace with a fast-moving field. I believe, though, that there are tremendous opportunities in India to motivate and work with enthusiastic young people. And I have great respect for my Indian colleagues who live and work under rather difficult circumstances. I admire their creativity and dedication, and their effort.

So I think there are lots of things possible in India and I would love to be a part of it -- some day.

RELATED LINKS
Basic visual pathway
Pathways to the brain
Information about the brain for educators, parents and the general public

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