Brain repair in the 21st century The New Scientist

[Guest guest]

http://www.newscientist.com/nsplus/insight/future/svendsen.html

Thursday, 28 August

Second Session: Medicine

Chairperson: Professor Sir Arnold Burgen, Honorary Fellow, Darwin College

" Whatever the future holds, modern medicine, brain, and body repair, will

bring with them ethical and moral debates. How much of the brain can be

replaced before you require a new passport? How long can one person go on

replacing their own cells or organs? "

Brain repair in the 21st century

Dr Clive Svendsen

The human brain is a lump of jelly-like tissue weighing 1.5 kilograms,

suspended in a fluid-filled, bony cavity. Emerging from the base of the

brain is the spinal cord, a metre-long cable which forms connections with

all other parts of the body. Together, the brain and spinal cord form the

central nervous system (CNS) and control every aspect of our lives--from the

simplest thought to the most demanding activities. It was the precocious

development of the CNS in primates which enabled complex language to emerge,

and, in turn, human thought, consciousness and civilised societies.

But how does the brain work and what happens when it goes wrong?

Neuroscience has emerged as a defined area of biological research aimed at

exploring these issues. It approaches the subject from many angles, and

covers a wide range of disciplines including genetics, biochemistry,

anatomy, pharmacology, physiology, behaviour, and cell biology (if you're a

surfer, check out this address for more information on neuroscience:

neurosciences on the Internet home page:

http://ilsebill.biologie.unifreiburg.de/neuromirror/toc.htm.

I want to look at a new area of neuroscience which has changed the way we

think about the brain, wiped away well-established dogmas and set the stage

for new forms of therapy: brain repair and regeneration. But first, we're

going to need a few key definitions to help people outside the field get to

grips with this exciting, but complex area.

What's in a brain and where does it come from? The currency of the brain,

and every other organ in the body, is, of course, cells. It is easy to lose

sight of the fact that we are all derived from a single egg cell, sparked

into action by a single triumphant sperm. From this fertilised egg, a

cluster of dividing cells rapidly begins to organise into a hollow ball.

These cells are unique in that they hold the potential at this stage of

development to give rise to any tissue in the body, and are termed embryonic

stem cells. The brain and spinal cord develop from a specialised group of

cells within this hollow ball called neural stem cells.

While they divide, these neural stem cells do not appear to be specialised

in any way, but some stop dividing and begin to form a scaffold structure.

This scaffolding is unique in each brain region and serves as a template for

other cells to migrate along and then differentiate (basically, stop moving

and mature). The process of division, migration and differentiation

continues until discrete brain regions begin to take shape. Clearly, this is

an enormously complex event--eventually there will be more than 50 billion

individual cells settled into their specific locations. How they get to the

right places remains largely a mystery, but we do know a lot about what

these cells do as individuals.

The key cell which develops out of the neural stem cell pool, and which is

best known to most people, is the neuron or nerve cell. This consists of a

cell body with a single cable emerging from it which can, in some cases,

travel for over a metre. Nerve cells form the wiring system which allows

signals, called nerve impulses, to travel both from one brain region to

another, and all the way down the spinal cord. During development, the

connections nerve cells make with each will form the basis of how the brain

works-- rather like a circuit board for a radio.

A less well-known cell is the glial cell which derives from the Latin word

for " glue " . Glial cells come in two major flavours. The first is called an

astrocyte and this cell was often thought to act literally as a type of glue

in the brain, simply packing around all of the nerve cells and holding them

together. However, astrocytes are now know to have far-reaching functions,

some of which directly affect the transmission of nerve signals and are

therefore extremely important. The second flavour of glial cell is called an

oligodendrocyte (often shortened to oligo) which plays a crucial role in the

brain and spinal cord. Oligos are able to wrap around nerve axons, rather

like plastic insulation wraps around the electric cable to the toaster.

Nerve axons within the oligo sheath are able to transmit nerve impulses at a

faster rate and are protected from interference by their neighbours.

So what happens when the brain breaks down? This enormously complicated mass

of nerve cells and glia, interwoven into a functioning brain, can, of

course, be shattered by trauma or disease. A riding accident can compress or

sever the spinal cord; a blow to the head often leads to haemorrhaging and

damage to brain tissue underneath. In both these cases it may be possible to

prevent some of the damage by using drug treatment shortly after the

accident which prevents swelling and further damage to vulnerable nerve

cells. However, long-term damage is very likely if the trauma is severe. The

only hope left to this group of patients, who are often young and fit in all

other respects, is brain repair of some sort.

Multiple sclerosis, Parkinson's, Alzheimer's, Huntington's and motor neuron

disease are all neurodegenerative diseases involving the loss of specific

cells within the brain. In the ideal world, brain repair would not be

required for these disorders. By understanding the cause of the disease,

establishing early diagnostic tests and using highly specific drugs to block

cell death, it should be possible to prevent and eventually eliminate them.

There is a mass of descriptive data on genes linked to these diseases, and

on structural changes which occur in the brains of patients. However, there

is still no clear picture of which combination of chemicals, toxins or genes

is specifically responsible for triggering the cell death in these disorders

(but, of course, there is no shortage of theories). Although this may come

with the current boom in neuroscience research, it may be too late for the

millions of patients already in the later stages of these illnesses--and

waiting desperately for some sign of hope. Again, brain repair may be an

olive branch of hope for them to hold on to.

Can brains repair themselves? One of the central dogmas of neuroscience was

laid down at the start of the century by one of its most famous pioneers,

Santiago Ramon Cajal. Cajal suggested that everything must die in the adult

CNS and that nothing could be regenerated [1]. In the following years, it

looked as if he was right. A consensus emerged which suggested that humans

are born with a certain number of nerve cells which die slowly over time,

are not replaced by new nerve cells, and are incapable of regeneration

following damage. This did not bode well for patients with neurological

disorders. But opinion has shifted over the past few decades.

It had been known for some time that nerve cells outside the CNS (the

peripheral nervous system) could regenerate long distances following damage.

In an elegant series of experiments, Albert Aguayo showed that providing

glial cells from outside the CNS were available, nerve cells within the CNS

could grow and regenerate over some distance [2]. This suggested that rather

than nerve cells within the CNS being incapable of regeneration, they may

simply be in an environment which does not support regeneration. More recent

studies have shown that in addition to CNS nerve cells having the capacity

to regenerate, they may also be capable of self-replacement. In certain

regions of the rodent brain, some neural stem cells persists into the adult.

These adult neural stem cells are able to divide and migrate some distance

before turning into either neurons or glia and so may represent a source of

tissue for brain repair. The capacity for both regeneration and renewal in

adult CNS tissue has opened up a new area of neuroscience which has enormous

clinical possibilities. As yet these have not been realised for patients,

but as we enter the 21st century it is clear that we are not far from a new

age where the brain may be able to repair itself.

Brain transplants as a therapy for neurodegenerative diseases. Although to

some the idea of a brain transplant is itself science fiction, there are a

large number of clinical trials going on throughout the world where nerve

cells have been transplanted into patients. The archetypal disorder in which

brain transplants have been performed is Parkinson's disease

(http://neurosurgery.mgh.harvard.edu/oisacson.htm#abort). In this disorder,

a specific group of nerve cells at the base of the brain degenerate, leading

to a lack of a chemical called dopamine which is made by neurons and

important for transmitting signals. This leads to tremor, inability to

initiate movement, postural changes and periods of " freezing " where the

patient is physically trapped in their own rigid body. Although some drugs

which imitate or stimulate dopamine within the brain do help with the early

stages of the disease, they lose effectiveness later and have serious side

effects.

Based on pioneering animal work by Anders Bjorklund and his colleagues, a

group in Sweden took live nerve cells from a developing human brain and

transplanted them into the brain of a Parkinson's patient [4].

Unfortunately, adult nerve cells could not survive the process of being

removed from the brain and so a system similar to kidney or heart donors was

impossible to instigate. The idea underlying this form of brain repair was

simple. Replace the nerve cells which had died in the disease with new ones

which could release the appropriate chemical--in this case, dopamine. Even

though the task was complicated by limitations in restoring normal circuits

within the Parkinson's brain (the new brain cells are put into the region of

the brain where dopamine is normally released, not where the dopamine cells

bodies are located), early results suggested a strong positive effect of the

transplants--although clearly there were some facets of the disease such as

tremor which did not respond to the grafts.

Since the early Swedish study, a number of groups around the globe have

tried this technique. It is fair to say that the most recent patients are

responding well to the transplants, many are reducing their drug levels and

showing significant improvements in tests designed to follow the course of

Parkinson's disease. As these patients are followed into the 21st century,

time will reveal the success of this form of brain repair. In the future,

improvements in the transplant protocol should produce greater clinical

benefit for patients. However, using human fetal tissue raises both ethical

and practical issues which preclude this type of therapy from becoming

widespread. This has led to a search for alternative sources of cells.

Ideally, cells for brain repair should be human in origin to avoid rejection

and be able to undergo essentially continuous expansion in the test tube to

provide the large number of cells required to provide transplants to

thousands of patients. Although many types of cell are currently being

explored, one source is the neural stem cell mentioned earlier. Neural stem

cells can divide in a test tube and after a number of weeks a single cell

can give rise to thousands of daughters [3,5,6]. Once expanded, human neural

stem cell populations can differentiate into nerve cells and glia--and

survive transplantation [7].

These cells, or others like them, may eventually replace fetal tissue and

bring neural transplantation into the reach of many more Parkinson's

patients. However, more work needs to be done to generate the appropriate

type of nerve cells from the stem cells and many laboratories are hard at

work worldwide [8],

Neural transplants, or perhaps more accurately cell replacement therapy, is

being considered for many other neurodegenerative disorders. The major

diseases under consideration are Huntington's, Alzheimer's and multiple

sclerosis--all of which involve the loss of specific sets of nerve cells or

glia which can potentially be replaced with transplants. Patients with

spinal injury may also benefit, where transplanted cells are used to

" bridge " the area of damage within the spinal cord and allow regeneration to

occur.

Having discussed what is presently happening, or about to happen in the

field of brain repair it's time to speculate about the future. But first,

fast backwards to 1973. I feel sure that if you had asked a neuroscientist

then if we would still be struggling with understanding the causes of

Parkinson's disease in the year 2000 the answer would have been " of course

not, by then we will have both a cause and cure " . But we haven't and there

isn't. The 50 billion or so individual cells within the brain may take a

while longer to give up their secrets. Our understanding of the nervous

system is definitely progressing exponentially, but nobody is really sure

whether we are presently on the flat or steep part of the curve. But let's

speculate anyway.

There will clearly be a place for brain repair. There will undoubtedly be

advances in stimulating the brain's capacity to repair itself, by recruiting

cells or encouraging regeneration of existing nerves. But closer to the

clinic, I would predict that alternative sources of cells will become

available which can be expanded indefinitely in test tubes. These will then

be matured into nerve cells or glia appropriate for restoring function in

various neurological diseases or trauma-induced injury.

Indeed, this may also be true for other cell types such as skin and blood

cells. Even whole organs may be " manufactured " in the test tube from

designer cells and used as " replacement parts " for an ageing or sick

population (although a whole brain may be more difficult to imagine then say

a whole kidney). To some this represents the ultimate nightmare: the

sanctity of human life reduced to its most basic cellular units. To others

these new discoveries represent a significant medical advance the ultimate

biological challenge: understanding how a mosaic of billions of individual

units can work together and produce a human being.

Whatever the future holds, modern medicine, brain, and body repair, will

bring with them ethical and moral debates. How much of the brain can be

replaced before the person requires a new passport? How long can one person

go on replacing their own cells or organs? Will this type of medicine lead

to the end of evolutionary pressures which have shaped our humanity? Big

questions and big science. But for those with relatives suffering from CNS

diseases or trauma, these questions have no meaning. If brain repair can

improve the life of their loved ones, then it has to be the answer.

Bibliography

1. Cajal, R. Degeneration and regeneration of the nervous system (Oxford

University Press, London, 1928)

2. , S. and Aguayo, A.J. " Axonal elongation into peripheral nervous

system bridges after central nervous system injury in adult rats " (Science,

vol 214, p 931)

3. Gage, F.H., Ray, J. and Fisher, L.J. " Isolation, characterisation, and

use of stem cells from the CNS " (Annual Reveiw of Neuroscience, eds W.M.

Cowan, E.M. Shooter, C.F. s and R.F. , Annual Reviews Inc,

Palo Alto, p 159)

4. Lindvall, O., Brundin, P., Widner, H., Rehncrona, S., Gustavii, B.,

Frackowiak, R., Leenders, K.L., Sawle, G., Rothwell, J.C., Marsden, C.D. and

Bjorklund, A. " Grafts of fetal dopamine neurons survive and improve motor

function in Parkinson's disease " (Science, vol 247 p 574)

5. McKay, R.D.G. " Stem cells in the central nervous system " (Science, vol

276, p 66)

6. Reynolds, B.A. and Weiss, S. " Generation of neurons and astrocytes from

isolated cells of the adult mammalian central nervous system " (Science, vol

255, p 1707)

7. Svendsen, C.N., Caldwell, M.A., Shen, J., ter Borg, M.G., Rosser, A.E.,

Tyers, P., Karmiol, S. and Dunnett, S.B. " Long-term survival of human

central nervous system progenitor cells transplanted into a rat model of

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© Copyright New Scientist, RBI Limited 1999