Neuroscience in the future

Max Bennett spoke with Susan Williamson about what's in store for neuroscience in coming years.

WILLIAMSON: What do you think will drive the neurosciences forward in the next 10 or 20 years?

BENNETT: I think the foundations put in place by the human genome project and spinning out of that the utilisation of molecular genetics, for example mining for genes, will drive things forward.

As a consequence of what has occurred since the human genome project and the genome projects from mice and rats and interesting experimental animals, we have a solid foundation on which to work.

We have very powerful molecular genetic techniques now, where we can mine for genes, etc. And we have micropositron emission tomography instruments where we can examine a mouse's brain activity - a mouse that has been derived from a stem cell that has had a particular gene put in it with a particular mutation, which is of interest to us because of our mining of the human genome in relation to say, schizophrenia.

So we have a barrage now of technologies, of course we have the standard chips of cDNA. But I would say at present there is at the most a glimpse of light at the end of the tunnel in identifying genes associated with something like schizophrenia. Schizophrenia is almost certainly a group of diseases, not one disease.

And multigenetic malaises like that, and manic depression and clinical depression, these are very complex disorders, we're not just looking for one gene we are looking for a combination of genes on different chromosomes with different kinds of mutations and that's complex work. And of course it's not just about genes, environment comes into it and so we have to mine the environmental circumstances that push an individual with the appropriate genetic profile for going say to schizophrenia.

You can have a genetic predisposition, for example in clinical depression, but you have to have an environmental circumstance as well, which in this case is an emotional environmental circumstance, such that it will impact on you dramatically and, depending on your genetic predisposition, you will go one way or another.

It's going to be very complex because these are unequivocally multigenetic diseases, so there is going to be a mixture of things.

Do you see that in the future diseases, such as clinical depression, will be successfully treated?

Getting the story straight for neuroscience in impacting the greatest of diseases facing humanity, which is clinical depression, is not going to be a bed of roses, it's a complex phenomenon.

Eight per cent of humanity suffers from the great psychiatric diseases, such as clinical depression (5 per cent), the psychoses such as schizophrenia (~1 per cent) and bipolar manic depression (~1 per cent). This group of maladies is by far one of the largest group of problems associated with brain function. The WHO has predicted that by 2020 the greatest debilitating factor to humanity will not be ischemic heart disease, it will be clinical depression.

Although there has been a shift in our image of those suffering from these great psychiatric malaises, we are still stuck with the 2000-year-old attitude towards people who are suffering these conditions, namely, that they are, in some sense, incapable of bringing appropriate self control to bear.

We are moving, but the movement is very slow. That's the basis of the future.

So you think there is a shift in recognising that the brain is an organ of the body that also gets sick?

I think there is a shift happening, but the amount of work that has taken to produce the shift has been enormous.

Even among Rhodes scholars and extremely intelligent people, as a consequence of their apparent lack of knowledge of the subject and their concern about something Orwellian occurring where we put antidepressants in the drinking water routine, they still cling dear to an attitude which I think is extremely painful for those suffering from these diseases, schizophrenia, manic depression or clinic depression.

One thing that has occurred in the last 50 years is the realisation, from at least certain sections of the population, that the synapse can be lesioned in the same way in a sense that Galen observed over 2000 years ago that the entire brain can be lesioned, in that case by a gladiatorial axe.

But now it is something much more sensitive, if you like, and with a much higher resolution, a chemical lesion to a particular very tiny part of the brain. Not something occupying 10 or 12 centimetres of cortex, but something occupying about one thousandth of a millimetre, a micron.

And it's at that level of resolution, at that level of lesion that we are now looking at in terms of these great psychiatric diseases.

Do you see that in the future we will have an understanding of how the brain functions and therefore what makes a person behave 'normally' or 'abnormally'?

Well, we don't know. Even the wiring of the retina, which is the most accessible part of the brain, although we know a fair bit about it we don't know a very large amount about it.

So when you come to the question of where are the networks, let alone how the networks work that have to be working normally in order for you to express the normalcy of an emotional life that is reasonable -- we haven't got a clue.

And we are certainly many generations away from having a clue about what are the networks that have to be operating normally and what are the actual connections within those networks that allow you to express the psychological capacity that you have.

What about the future for neuroscience outside these major psychoses? Like neural stem cells or other research areas?

I do tend to dwell too much on the difficult job of facing up to the great psychoses, but there are angles opening with glial cells for example, and stem cells, which are very exciting.

Until 1990 the glial cells were considered extremely boring. They were called glia, which is Greek for glue, because that's all they did they just stuck in between the neurons, which is where all the action was.

We now know that glial cells are also conducting and transmitting, but they're not conducting and transmitting electricity, they're conducting and transmitting waves of calcium change inside the cell. And happily enough, the glial cells are forming connections with each other as well as with neurons, and they are using propagation of calcium waves to transfer information around the brain.

I think this is and will be a huge area of investigation. Many of the activities in our lives are not working in the hundred-millisecond or tens-of-millisecond time domain, this is the time domain of the electrical pulses that travel down nerves to move your hand or arm are. But thinking is in a different time domain, in the tens-of-seconds time domain, which is what glial cells work in. Their waves are propagating in that sort of time scale two orders of magnitude, or three at the least, slower than the nerves are working in.

I think research on glial cells will continue to be a huge area of investigation. Glial cells make up 70 per cent of the brain, and one thing we haven't been able to do yet is non-invasive imaging of the glial networks and the propagation of information through their internal calcium wave system. It's a new ball game, which will be fascinating when it opens up.

And stem cells?

I am boggled and chagrined at the fact that stem cells are magically doing so much. I did think that it was ludicrous that stem cells could be dropped into the spinal cord after a partial lesion and that they were going to rectify things somehow. As an old reductionst, I just want every little bit of the story to be put in place. Stem cells are doing extraordinary things!

And of course something that was totally set in concrete in principle that I've taught for the last 45 years was that once you are born you have a certain set of neurons and all that's going to happen is that you are going to lose them. We know now that this is not true, we know that in the hippocampus you are making new neurons all the time, particularly in one part the dentate gyrus -- the stem cells are there making new neurons.

And certainly in the mammals that we have looked at so far, physical exercise and a novel environment increases the rate at which stem cells will form new neurons in the hippocampus. These are extraordinary revelations.

Max Bennett is head of The Neurobiology Laboratory at the University of Sydney.